Genomic Structure and Variation of Nuclear Factor (Erythroid

Hindawi Publishing CorporationOxidative Medicine and Cellular LongevityVolume 2013 Article ID 286524 24 pageshttpdxdoiorg1011552013286524

Review ArticleGenomic Structure and Variation of Nuclear Factor(Erythroid-Derived 2)-Like 2

Hye-Youn Cho

Laboratory of Respiratory Biology National Institute of Environmental Health Sciences National Institutes of Health111 TW Alexander Dr Building 101 MD D-201 Research Triangle Park NC 27709 USA

Correspondence should be addressed to Hye-Youn Cho cho2niehsnihgov

Received 11 February 2013 Accepted 22 April 2013

Academic Editor Mi-Kyoung Kwak

Copyright copy 2013 Hye-Youn Cho This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

High-density mapping of mammalian genomes has enabled a wide range of genetic investigations including the mapping ofpolygenic traits determination of quantitative trait loci and phylogenetic comparison Genome sequencing analysis of inbredmouse strains has identified high-density single nucleotide polymorphisms (SNPs) for investigation of complex traits which hasbecome a useful tool for biomedical research of human disease to alleviate ethical and practical problems of experimentation inhumans Nuclear factor (erythroid-derived 2)-like 2 (NRF2) encodes a key host defense transcription factor This review describesgenetic characteristics of human NRF2 and its homologs in other vertebrate species NRF2 is evolutionally conserved and sharessequence homology among species Compilation of publically available SNPs and other genetic mutations shows that humanNRF2 is highly polymorphic with a mutagenic frequency of 1 per every 72 bp Functional at-risk alleles and haplotypes have beendemonstrated in various human disorders In addition other pathogenic alterations including somatic mutations andmisregulatedepigenetic processes in NRF2 have led to oncogenic cell survival Comprehensive information from the current review addressesassociation of NRF2 variation and disease phenotypes and supports the new insights into therapeutic strategies

1 Overview

The gene nuclear factor (erythroid-derived 2)-like 2(NFE2L2) or more commonly the used synonym nuclearfactor erythroid 2- (NF-E2-) related factor 2 (NRF2) andits mouse homolog (Nfe2l2 Nrf2) encode a ubiquitoustranscription factor belonging to the basic leucine zipper(bZIP) protein family [1 2] NRF2 modulates downstreamgenes by binding to their cis-regulatory module antioxidantresponse elements (AREs) NRF2 targets include ARE-bearing effector genes such as reactive oxygen species (ROS)scavenging enzymes (eg superoxide dismutases SODs)phase-2 defense enzymes (eg glutathione-S-transferaseGST heme oxygenase-1 HO-1) drug efflux pumps(eg multidrug resistance proteins MRPs) and variousinteracting and indirectly modulated proteins [3ndash6] TheNRF2-ARE pathway has emerged in mechanisms of humandiseases in which oxidative stress is implicated Importantly

three lines of gene-targeted (knockout) mice weregenerated by Drs M Yamamoto (Nfe2l21199051198981119872119910119898) Y W Kan(Nfe2l21199051198981119884119908119896) and P A Ney (Nfe2l21199051198981119873119890119910) [7ndash9] and 124gene-trapped or gene-targeted cell lines have been established(httpwwwinformatics jaxorgsearchesallele reportcgimarkerID=MGI108420) During the last decade or morewide application of the knockout mice to human diseasemodels has led to new insights into disease pathogenesis andtherapeutic potential (Figure 1)

Kelch-like ECH-activating protein 1 (KEAP1 for humansKeap1 for mice or iNrf2 for rats) is a cytoplasmic suppressorof NRF2 and is critical in NRF2 homeostasis and activity [10]Substantial efforts have led to the discovery of the molec-ular mechanisms of KEAP1-mediated NRF2 regulation Inunstressed conditions the NRF2-bound KEAP1 homodimeris complexed to a ubiquitin ligase (Cullin 3-based E3 ligase)which polyubiquitinates NRF2 for proteasomal degradationand maintains NRF2 homeostasis (20min half-life of cellular

2 Oxidative Medicine and Cellular Longevity

Carcinogenesis

Mammary carcinoma (+)Urinary bladder carcinogenesis (+)

Skin tumor (+)

Kidney and bladder

Diabetic nephropathy (+)As toxicity (+)

Brain and neuromuscular systemIschemic brain injury (+)

Cerebral ischemia and stroke (+)Hearing loss and ototoxicity (+)

AirwaysAcute lung injury (+)COPDemphysema (+)Allergy and asthma (+)Pulmonary fibrosis (+)

Steroid resistance (+)

Inflammationimmunity and developmentSepsis (+)Autoimmune encephalomyelitis (+)Rheumatoid arthritis and cartilage destruction (+)

Heart and circulation

Hemolytic anemia (+)

MetabolismLipid homeostasis (+)

Glucose homeostasis (+)

Skin and eyeSkin healing (+)

Uveitis (+)

GastrointestineAlcoholic liver injury (+)

Acetaminophen hepatotoxicity (+)Bile acid homeostasis (+)

Colitis (+)

Various xenobiotic toxicity (+)Cholestatic liver injury (+)

Steatohepatitis (+)Gastroparesis (+)Liver fibrosis (+)

Acute intestinal mucosal injury (+)

Traumatic brain injury (+)

Spinal cord injury complications (+)

Brain leukoencephalopathy with astrogliosis (+)Gliosis and dopaminergic nigrostriatal degeneration (+)Intracerebral hemorrhage-induced brain injury (+)

Cardiac hypertrophy (+)

Ischemia-induced neovascularization (+)Atherosclerosis (minus)

Lupus-like autoimmune nephritis (+)Spermatogenesis (+)

Gastric neoplasia (+)Colorectal cancer (+)

Lung adenomas (minus)

Pseudomonas aeruginosa infection (+)

Bronchopulmonary displasia (+)Respiratory syncytial virus disease (+)

High-fat-diet induced obesity (+)

UV-induced skin aging (+)

Retinal ischemia-reperfusion (+)Retinopathy of prematurity (+)

Ischemic nephrotoxicity (+)Cisplatin nephrotoxicity (+)

Pollutant (diesel exhaust O3) toxicity (+)

Parkinsonrsquos disease (+)

Nrf 2

Cardiomyocyte damage (+)

Figure 1 Role of Nrf2 in human pathogenesis learned from model studies using mice genetically deficient in Nrf2 (+) indicates protectiveor beneficial effects and (minus) indicates aberrant roles

NRF2 [11]) However modifications of KEAP1 (eg cysteineresidues) and NRF2 (eg serine residues) under stressedconditions activate NRF2 by liberating it from a ldquohinge andlatchrdquo NRF2-KEAP1 affinity binding allowing its nucleartranslocation [12]

In the current review I address genetic aspects of humanNRF2 and its homologs in other vertebrate species Sequencevariations in humanNRF2 andmurineNrf2 including single-nucleotide polymorphisms (SNPs)were collected frompublicdatabases and compiled Mutations that have been associatedwith disease risks are defined Nongenetic variations includ-ing somatic mutations and epigenetic modifications are alsodescribed Although the current review does not deal withmutations in other species recent characterization of nrf2mutant zebrafishwhichwere hypersensitive to environmentaltoxicants [13] also provides a useful investigational tool

2 Sequence of NF-E2-Related Factor 2and Cross-Species Homology

Homology scores of gene (coding DNA sequences cds) andprotein across 10 species were compared with human NRF2The highest sequence homology (98-99) was with chim-panzee and rhesus monkey while the lowest similarity wasfound with zebrafish (Table 1) While there is approximately

about 83 homology in cds and protein sequences of humansand rodents 51015840-untranslated regions (51015840-UTR UTR-5) ofthese strains extend differentially (114 bp in human 233 bp inmouse and 82 bp in rat) and the human 51015840-UTR does notshare significant sequence homology with either rat ormouse(the rat is 94 homologous with the 31015840 portion of mouse 51015840-UTR)

Human NRF2 is located in the cytogenetic band 2q312of chromosome 2 spanning 178095031ndash178129859 bp as acomplementary sequence (gene ID 4780 Table 1) MurineNrf2 maps as a complementary sequence to chromosome2 C3 (4475 centimorgan) and spans 75675519ndash75704641(gene ID 18024 Table 1) The complete cds of NRF2 is2859 bp and there are 14 transcript variants reported(httpuseastensemblorgHomo sapiens) Mouse Nrf2mRNA spans 2469 bp and another variant has been re-ported (httpuseastensemblorgMus musculus) The hu-man NRF2 protein (ID NP 006155) contains 605 amino acid(aa) residues with molecular weight of 677 kDa (isoform1) and total 12 isoforms are published (the National Centerfor Biotechnology Information NCBI httpwwwncbinlmnihgovrefseqrsg eEnsemble httpuseastensemblorgindexhtml UniProt Consortium httpwwwuniprotorguniprotQ16236 httpwwwuniprotorguniprotQ60795)Mouse Nrf2 protein (ID NP 035032) comprises 597 aa at668 kDa (Table 1) Structurally there are 6 NRF2-ECH

Oxidative Medicine and Cellular Longevity 3

Table1Geneo

rtho

logy

ofNF-E2

-related

factor

2acrossthes

pecies

Species

Hum

anHom

osapiens

Cat

Felis

catus

Chim

panzee

Pantro

glodytes

Dog

Canislupus

familiaris

Cattle

Bostaurus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdashGenes

ynon

yms

NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2Ch

romosom

emap

2q312

C12B

362

Genom

esequence

(NCB

IBuild)

NC

0000

0211

(GRC

h37p

10)

NC

1087301

(Feliscatus-62)

NC

0064703

(Pan

troglod

ytes-214)

NC

0066183

(CanFam31)

AC00

01591

(Bos

taurus

UMD

31)

Prim

arysource

HGNC

7782

mdashmdash

mdashBO

S1716

GeneID

mapping

(orie

ntationlowast

)

4780

178095031minus178129859(minus)

1010

9881

2165356974minus

165392728(minus)

7426

22181721941minus181756837(minus)

4788

1320989206minus21021893

(minus)

4970

2419659540minus19692048

Ensembleg

eneID

(mapping

)EN

SG00

00011604

4(178092323minus178257425)

mdashEN

SPTR

G00

000012677

(181721949minus181756285)

ENSC

AFG

0000

0013506

(20987569minus

21022230)

ENSB

TAG00

000019255

(19659540minus19692048)

RefSeq

IDm

RNA

size

NM

006164

4(G

I372620346)2859b

p

XM0039908931

(GI410968909)

predicted2394

bp

XM00114

58762

(GI332814815)predicted

2850

bp

XM5359753

(GI345797173)

predicted2570

bp

NM

0010116

782

(GI147904941)240

9bp

ProteinID

(aaMW

sect )NP00

61552

(60567696)

XP0039909421

(60667797)

XP00114

58762

(60567686)

XP5359751

(60167087)

NP0010116

782

(60767813)

UniProt

IDQ16236

mdashA2T

6Y9

mdashQ5N

UA62

Varia

nts

14transcrip

ts12

isoform

s3transcrip

ts3iso

form

s5transcrip

ts5iso

form

s2transcrip

ts2iso

form

smdash

Hom

olog

ygeneprotein

100100

893914

999999

893888

905891


Table1Con

tinued

Species

Rhesus

mon

key

Macacamulatta

Chicken

Gallusgallus

Zebrafish

Daniorerio

Mou

seMus

musculus

Rat

Rattu

snorvegicus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2nu

clear

factorerythroid-derived

2lik

e2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdash

Genes

ynon

yms

NFE

2L2NRF

2Mmu966

NFE

2L2NRF

2nfe2l2N

rf2N

rf2a

wufc15g09wufj6

7e03

Nfe2

l2N

rf2A

I194320

Nfe2

l2N

rf2

Chromosom

emap

127

92C

3(4475

cM)

3q23

Genom

esequence

(NCB

IBuild)

NC

0078691

NC

0060

943

NC

0071205

(Zv9)

NC

0000

687

(GRC

m38p1)

NC

0051023

(Rno

r50)

Prim

arySource

mdashCG

NC

4960

4ZF

INZ

DB-GEN

E-030723-2

MGI108420

RGD620360

GeneIDmapping

(orie

ntationlowast

)70

7606

40848940minus40

8846

00(minus)

3960

1415304546minus15320356

3601

491643746minus

1670288

1802

475675519minus757046

41(minus)

8361

969041647minus69069070

(minus)

Ensembleg

eneID

(mapping

)EN

SMMUG00

0000

01861

(40848948minus

40884174)

ENSG

ALG

0000

0009240

(16897956minus

16922637)

ENSD

ARG

0000

0042824

(1643631minus1672715)

ENSM

USG

0000

0015839

(75675513minus

757046

41)

ENSR

NOG00

0000

01548

(58366

693minus

58394118)

RefSeq

IDm

RNA

size

NM

0012576071

(GI383872375)2335b

pNM

2051171

(GI45384113)2555

bpNM

1828891

(GI33504557)2149

bpNM

0109023

(GI76573877)2469

bpNM

0317892

(GI402692377)2305b

pProteinID

(aaMW

sect )NP001244

5361

(606

67703)

NP9904

481

(58265160)

NP8783091

(58665757)

NP0350321

(59766770)

NP1139771

(59766825)

UniProt

IDF7GPD

8Q90834

Q8JIM

1Q60795

O54968

Varia

nts

2transcrip

ts2iso

form

s1transcript1isoform

1transcript1isoform

1transcript

1transcript1isoform

Hom

olog

ygeneprotein

988990

726674

546491

834825

838832

Referto

httpwwwncbinlm

nihgovhom

ologene2412

and

reference

[14]forcross-speciesho

molog

yDetails

ofho

molog

yscores

and

sequ

encescan

bealso

obtained

byblastagainsthu

man

sequ

ence

(http

blastn

cbin

lmnihgov)

Furtherinform

ation

ontranscrip

tvaria

ntsand

protein

isoform

sareview

able

bygene

IDat

NCB

I(http

wwwncbinlm

nihgovrefseqrsg)

and

eEn

semble

(http

useastensembleo

rgin

dexhtml)or

byproteinID

atUniProt(http

wwwun

iproto

rg)

sect MWpredicted

molecularweightfrom

NCB

I(MW

inUniProtvarie

sslightly)Re

fSeqreference

sequ

enceaaam

ino

acidsandlowastgene

incomplem

ento

rientation


Table 2 Protein domains of NF-E2-related factor 2

Domains Amino acid positionslowast Predicted functionsHuman (605 aa) Mouse (597 aa)

Neh216ndash89

DLG motif 17ndash32ETGF motif 77ndash82

16ndash89 KEAP1 repression through DLGETGF motif-DC motif binding fastredox-sensitive proteasomal degradation

Neh4 111ndash134 111ndash134 Translocation and transactivation Phosphorylation or CBP bindingNeh5 182ndash209 172ndash201

Neh6 337ndash394(or 338ndash388) 328ndash385 Degron motif-associated constitutive turnover slow redox-insensitive

(Keap1-independent)

Neh1435ndash568

basic motif 503ndash518leucine zipper 525ndash539

427ndash560basic motif 494ndash509leucine zipper 517ndash531

Dimerization for nuclear translocation DNA binding through basicmotif-leucine zipper

Neh3 569ndash605 561ndash597 CHD6 binding stability or transactivationlowastVaries slightly among publications

homology (Neh) domains configuring the protein sequenceof either species (Table 2) and the potential functions of eachregion particularly the highly conserved KEAP1-bindingNeh2 and DNA- (ARE-) binding Neh1 domains have beenintensively investigated [12 14 15]

3 Genetic Variation of NF-E2-Related Factor 2in Human and Mouse

31 Evolution Genome Sequence and Polymorphism Dis-covery in Human and Mouse While rare and monogenicMendelian diseases are inheritable mutations in a single gene[16] many common diseases are complex traits and thedisease phenotypes are affected by variants inmultiple geneticloci Recent advancements in high-throughput technologyhave enabled sequencing of entire mammalian genomes[17ndash19] and information on DNA sequence and variationhas facilitated the study of complex traits of human dis-orders Genome-wide association studies (GWAS) examinewhether SNPs are associated with important disease traitsand ascertains ldquoat-riskrdquo genotypes that are significantly moreprevalent in the affected group than in the nonaffected groupThe HapMap Project (httphapmapncbinlmnihgov) hasmapped combinations of alleles at specific loci (haplotypes)that is common patterns of sequence variation in severalhuman populations It has supported efficient mapping ofmultiple loci for complex traits in GWAS Candidate geneapproaches based on findings from GWAS of similar dis-orders have also been useful for determining the potentialgenetic mechanisms of diseases

The evolutionary divergence of human and mouse lin-eages occurred for roughly 75million years and their genomesequences have been altered by nearly one substitution (ordeletion or addition) for every twonucleotides [20]Howeverthis slow evolution process resulted in a high degree ofconservation across the two species which allows alignmentof orthologous sequences gt90 of the human and mousegenomes is partitioned into corresponding regions of con-served synteny and at the nucleotide level approximately 40of the human genome is aligned to themouse [20]Due to this

fact biomedical studies of human genes are complemented byexperimental manipulation of corresponding mouse genesand they have aided functional understanding of genesin human health Following the 2003 completion of theHuman Genome Project of approximately 31 giga base pairs(Gbp) the Mouse Genome Project assembled the completegenome sequence of one strain (C57BL6J 2716965481 bp)in 2011 Using this reference strain whole genome sequenc-ing data across 16 additional inbred strains were done(httpwwwsangeracukresourcesmousegenomes [21])Discovery of high-density SNPs in the mouse genome sup-ports evolutionary history of the strain and provides a toolto investigate models of human disease processes that cannotoften be practically achieved through direct human studies

32 GeneticMutations in HumanNRF2 HumanNRF2 codesthree major isoforms of protein (Figure 2) Transcript variant2 (NM 0011454122 2746 bp) has an alternate promoter 51015840-UTR and a downstream start codon compared to variant 1(NM 0061644 2859 bp) It encodes an isoform 2 missing N-terminal 16 aa (NP 001138884 or Q16236-2 589 aa) relativeto isoform 1 (NP 0061552 or Q16236 605 aa) Isoform 3(NP 0011388851 or Q16236-3 582 aa) is encoded by tran-script variant 3 (NM 0011454132 2725 bp) and lacks aninternal segment relative to isoform 2 due to an alternate in-frame splice site in the 31015840 coding region In public databasesmore than 583 sequence mutations are reported in NRF2(34827 bp) and 7000 bp upstream (Table S1 data acquired asof December 2012) (See Table S1 in Supplementary Materialavailable on line at httpdxdoiorg1011552013286524)NRF2 locates on 178130354-178129304 bp of GRCh37p10PrimaryAssembly and Figure 2 shows sequences of proximalpromoter (minus1 to minus500) partial mRNA variant 1 including 51015840-UTR (exon 1 up to TSS) and protein isoform 1 (NP 006155encoded by variant 1 NM 0061644 556ndash2373 bp) Basedon the current assembly and sequence update previouspromoter positions minus686 [22]minus653 [23] are identified asminus214 minus684 [22]minus651 [23] as minus212 and minus650 [22]minus617 [23]asminus178Overall frequency ofNRF2 SNPs and othermutationsis about 1 per 72 bp The genetic mutations include 37 in


Translation start site for variants 2 and 3

1 missed in isoforms 2 and 3pA72T pS99P pQ121H missed in isoform 3

pP406S pE423D pK428R pR437W pR449C

minus400

minus500

minus50minus100

minus200

minus300

minus450

minus350

minus250

minus150

g minus

g

pE152K pV155I pL177V

pV268M

pR517K pH453L

pS365I pS387N pK389R pL309F pI317M pD341V

pK219R pP233S pK237 = fs

51101151201251301351401451501551601

Protein isoform 1 (NP 006155)

g minus66minus65insC

Termination codon (c +2371 +2373)

Translation start site (c +1)

151

101151201251301351401451501551601

2351

frame stop codonc minus156 154 in-old + 1 [23]

old + 1 [22]

g minus1 (178130354)

c minus96delC

c minus438 minus437delTT

minus89 minus87delGCC

transcription start site)+1 (c minus555

p R43Q p R43W

Genomic DNA (reversed contig GRCh37 p10 primary assemblyNM 0061644)minus477

minus214 g minus212gminus188

c 9minus95

g minus178

c minus304

c 8minus13

c 2minus16

TgtA

CgtT

GgtA

GgtA

GgtA

GgtT

GgtCAgtG

AgtCAgtG

Figure 2 DNA (variant 1 partial promoter and exons 1 and 5) and protein (isoform 1) sequence of Human NRF2 SNPs and amino acidresidues for nonsynonymous SNPs are marked

the 51015840 flanking promoter and 59 in exons (Tables 3 and S1)Among exon SNPs 26 are nonsynonymous (Cns) mutationsA triplet repeat variation (rs143406266 GCC

4versus GCC

5

previously published as minus20minus6) in the 51015840-UTR was uniquelyidentified in Asian populations [22 24]

33 SNPs Haplotypes and Association with Disease RiskThe use of gene knockout mice in model systems hasprovided potential insights into the role of NRF2 in thepathogenesis of various human disorders (see Figure 1)Recent epidemiological and association studies have revealedsignificant associations of NRF2 sequence variations withdisease risks which further supportsNRF2 as a susceptibilitygene Most of the phenotype-associated variants are in thepromoter region and presumed to be involved in NRF2 generegulation Table 4summarizes NRF2 SNP andor haplotypealleles that have been associated with oxidant-related diseaserisks Interestingly there is no evidence for exon SNPs as at-risk alleles For convenience and consistency intronic and31015840 distal SNP alleles are presented as chromosome contig(HGVS) alleles while promoter and exon SNPs are presentedas reversed contig alleles throughout the text

Pulmonary Diseases NRF2 SNPs in the promoter and intron1 sequences have been investigated for their potential asso-ciations with risk of pulmonary critical disorders includingacute lung injury (ALI) cigarette smoke-induced chronicobstructive pulmonary disease (COPD) and asthma Aheterozygous CA SNP at minus178 position (rs6721961TgtCor TgtG previously minus617 or minus650) significantly increasedthe risk for developing ALI following major trauma inEuropean and African-American populations (odds ratioOR 644 95 confidence interval CI 134ndash308 allelicfrequency = 119 at 21180) [23] Promoter activity ofthe A allele (AC or AA) determined in vivo and invitro was significantly lower than CC allele at that locus(minus178 in an ARE-like motif) indicating that it is a func-tional SNP for autoregulation [23] The minus178GG werealso nominally associated with ALI-related 28-day mor-tality following systemic inflammatory response syndrome[37] In a Japanese cohort SNP haplotype (rs2001350Trs6726395Ars1962142Ars2364722Ars6721961T) co-tainingthe minus178AA homozygote was associated with an annualdecline of rapid forced expiratory volume in one second(FEV1) in relation to cigarette-smoking status [34] In addi-

tion a promoter and 51015840-UTR SNP haplotype consistingof minus214G allele (52 rs35652124 previously minus686minus653)

Oxidative Medicine and Cellular Longevity 7Ta

ble3Geneticmutations

inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG

cminus555-66minus555-65insC

51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA

cminus438minus437delT

Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC

cminus89minus87delGCC

Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT

clowast423lowast424d

elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou

sDaggerheterozygositydetectednano

tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H

pyloriinfection(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin

haplotype119875=0022

Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])

CI=minus6360simminus1780C

=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]

=currentlyminus214minus684in

reference[22]

=minus651inreference[23]

=currentlyminus212minus651inreference[22]

=minus617in

reference[23]

=currentlyminus178Ch

romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval


minus212GG (98 rs67006649 previously minus684minus651) minus178Callele (73) and GCC

4(53) was predicted to increase

respiratory failure development (hazard ratio = 095 CI091ndash099) in German COPD patients [32] Significant inter-action was also identified between an intronic SNP Gallele (rs6726395 g178103229AgtG 884 frequency) andsmoking status on FEV

1decline relative to the reference

AA allele in the above Japanese cohort [34] Siedlinskiet al [39] reported that the CC genotype of anotherintronic SNP (rs2364723 g178126546GgtC) was associatedwith a lower FEV

1level compared to the wild-type geno-

type (GG) in two Netherland cohorts (CI minus636minus178frequency = 0525 and pooled cohort size = 2542) ThisSNP alone or as a haplotype with 4 more intronic SNPs(rs13001694Grs1806649Trs4243387Trs6726395G)was alsoassociated with high FEV

1levels in individuals that ever

smoked [39] In a Hungarian population of childhoodasthma SNPs at minus178 (CA) and 31015840 flanking (rs2588882TG)loci were inversely associated with infection-induced asthma(OR 0437 CI 028ndash080 OR 0290 CI 013ndash062 resp) andthese SNPs significantly influenced an asthma-environmentalpollution interaction [38]The intronic SNP rs1806649 (CgtT)was associated but not significantly with an increased risk ofhospitalization during high-level particulate matter (PM

10)

periods in asthma or COPD patients (119899 = 209) of the UnitedKingdom (UK) [41] Asthma andCOPDadmission rateswererelated to the increase in environmental PM

10concentration

Importantly effects of interaction between prenatal stressand NRF2 SNPs on descendant pulmonary health wereinvestigated by the Avalon Longitudinal Study in the UKmaternal smoking during pregnancy was not associated withlung function change determined by maximum mild expi-ratory flow (FEF

25ndash75) or with asthma incidence in school-aged children and this relation was not modified by NRF2SNP genotypes [42]However early gestation acetaminophenexposure significantly influenced the risk of asthma andwheezing at the age of 7 years in gt4000 mothers and gt5000children [33] When maternal copies of the minus212A allele werepresent association with asthma (11374891 OR 173 CI122ndash245) and wheezing (11494949 OR 153 95 CI 106ndash220) was significantly increased [33]

Gastrointestinal Disorders While there was no evidence inlung cancer cases studies in Japanese populations suggesteda potential association of NRF2 variations with gastro-intestinal tumorigenesisHelicobacter pylori (H pylori) causesgastritis which can lead to gastric atrophy and cancer Ingastric epithelium from the Japanese cancer cohorts (39gastric cancers 46 controls) H pylori infection was posi-tively correlated with aberrant CpG island methylation oftumor suppressor genes (eg p14) and minus214Gminus212G orminus214Aminus212G NRF2 haplotype was significantly associatedwith increased (OR 290 95 CI 114ndash736) or decreased(OR 033 95 CI 013ndash088) risk of the CpG methyla-tion respectively in the H pylori-infected patients [29]Further study from the same investigators determined thatminus214Aminus212G allele carriers had significantly (119875 = 0022)reduced risk of gastric cancer inH pylori-negative cases [30]The minus214AGminus212AG genotypes were negatively associated

(OR 045 CI 022ndash093) and the minus214Gminus212G genotypeswere positively associated (chronic continuous phenotypeOR 257 CI 101ndash660) with ulcerative colitis (89 patients 141controls) in a Japanese population [31]

Autoimmune Disorders Systemic lupus erythematosus (SLE)is a long-term autoimmune disease more frequently found infemales than in males It affects organs including skin jointskidneys and brain and nephritis is an aggressive character-istic in some patients Genome-wide association studies inhumans identified a suggestive quantitative trait locus nearNRF2 [43] A study of a Mexican Mestizo population (362patients with childhood-onset SLE 379 controls and 212nephritis diagnosed) determined that lupus with nephritiswas significantly (OR 181 CI 104ndash312) associated with theminus214GA SNP in females [25] The same SNPs were notclosely associated with SLE risk in a Japanese cohort [22]Vitiligo is a skin condition in which there is a loss of browncolor (pigment) from areas of skin resulting in irregularwhite patches It is thought to be an autoimmune diseasecaused by loss of cells (melanocytes) that produce brownpigment A study indicated that theminus178A allele increased therisk of vitiligo dose-dependently (OR 1724 95 CI 135ndash221for CA OR 2902 CI 162ndash519 for AA) [35]

Female Disorders It is well known that estrogen metabolites(eg catechols) cause ROS formation suggesting correla-tion of NRF2 and downstream effectors in postmenopausalmammary cancer In a study of a Finish population (KuopioBreast Cancer Project 119899 = 452 patients 370 controls)the minus178AA homozygous genotype (OR 4656 CI = 135ndash1606) and 31015840 flanking rs2706110 (TT OR 2079 CI 118ndash368) genotype were associated with increased risk of breastcancer while the 51015840 flanking minus3306TT homozygous allelewas significantly associated with lower survival (frequency =71219 OR 1687 CI 1105ndash275) [27] suggesting that NRF2genetic polymorphisms affect susceptibility and outcome ofthe patients The minus178A allele carriers together with intronicrs1962142A allele carriers were associated with lowered tissuelevels of NRF2 proteins [27] In postmenopausal women theminus178A allele (OR 179 95CI 370ndash8570) appeared tomodifythe risk of venous thromboembolism caused by oral estrogentherapy (AA or AC frequency = 333) as demonstratedby the French ESTHER study (161 cases 474 controls) [36]An intronic rs1806649CgtT SNP did not associate with breastcancer risk in postmenopausal women [40] However whenthis SNP and other at-risk alleles of ARE-responsive genes(NQO1 HO-1 NOS3) were combined there was a significantgene-dose effect on the breast cancer risk [40] Althoughcoding region SNPs in NRF2 and KEAP1 were identifiedin the Japanese endometrial adenocarcinoma patients noassociation of NRF2 SNPs with the disease was found [44]

Neurodegenerative Diseases Oxidative stress is known to beinvolved in Parkinsonrsquos disease (PD) presumably due toproduction of ROS fromhigh-dopaminemetabolism and lowlevels of antioxidants in the substantia nigra of the brainInvestigators found a protective NRF2 haplotype consistingof four 51015840 flanking SNPs (minus5238Gminus214Aminus212Gminus178C)


and 4 intronic SNPs (rs2886161Ars1806649Ars2001350Ars10183914A) from Swedish (OR 09 CI 060ndash140) and Polish(OR 04 CI 030ndash060) populations (total 165+192 PD cases190+192 controls) [26]The investigators also suggested thatNRF2 haplotype alleles were associated with 2 years earlierage of Alzheimerrsquos disease (AD) onset 4 years earlier age ofposterior subcapsular cataract surgery and 4 years later ageof cortical cataract surgery while they were not significantlyrelated to AD or age-related cataract risk [45]

34 Genetic Mutations in Mouse Nrf2 Tsang et al [46]compiled 673 SNPs in 55 mouse strains and constructedtheir phylogenetic tree to correlate and clarify the originsof strains based on the assembled mouse genome sequenceand SNP data [20 47 48] Recently using the completegenome sequence of C57BL6J (B6) mouse as a referencehigh-density SNP screening in other laboratory strains orin panels of strains has been published (see [17]) Althoughmillions of mouse SNPs (gt10089892 as of December 2012)and haplotype mappings from more than 120 strains havebeen published as valuable references for dissecting thegenetic basis of complex traits [49ndash51] little attention hasbeen paid to polymorphisms of Nrf2 and their correlationwith disease phenotypes

Figure 3 demonstrates the proximal promoter region(minus1 to minus950)51015840-UTR (exon 1 up to TSS) and proteinsequence of mouse Nrf2 based on GRCm38p1 PrimaryAssembly (75704641ndash75675513 bp) mRNA variant1 and protein (NP 035032 encoded by NM 010902234ndash2027 bp) sequences Genetic variations in the Nrf2genome of inbred strains collected from public databasesare listed in Tables S2 and 5 (See Supplementary TableS2) Overall 968 genetic mutations are compiled forNrf2 gene and 5 kb upstream2 kb downstream regions785 SNPs between B6 and another 16 strains wereacquired from the Mouse Phenome Database (MPDhttpphenomejaxorg dbqrtn=snpret1) and additionalSNPs and other mutations were acquired from NCBI dbSNP(httpwwwncbinlmnihgovsnpterm=mus+musculus20nfe2l2) In total 132 mutations are in the promoter (37in proximal 1 kb) 49 in exons (38 in coding region 19 Cns)727 in introns and 60 in the 31015840 flanking region Excludingmutations in the 51015840 and 31015840 flanking sequences murine Nrf2sequences appear to be more highly variable (1 variationper 375 bp) than much of the mouse genome which has anapproximate frequency of one SNP per every 245 bp (httpwwwinformaticsjaxorgmgihomehomepagesstatsallstatsshtmlallstats snp)

Nrf2 was found to be a susceptibility gene from genome-wide linkage analysis in a murine model of hyperoxia-induced ALI [52] A promoter SNP minus103TgtC (previouslypublished as minus336TgtC) in Nrf2 was found and predicted toadd an additional Sp1 binding site in hyperoxia-susceptibleB6 mice but not in resistant C3HHeJ mice [52] Genotypesfrom the SNP and from simple-sequence length polymor-phism markers of the Nrf2 locus (D2Mit248 and D2Mit94)cosegregated in the B6C3F

2mouse cohort [52] and Nrf2

deficient mice were significantly more susceptible to ALI

sub-phenotypes caused by hyperoxia than similarly exposedwild-type mice supporting Nrf2 as a contributor to thephenotypic traits [53] Although no other functional analyseson Nrf2 SNPs or haplotype association studies have beenconducted in inbred mice strains bearing haplotypes suchas multiple Cns in functional domains (eg F71L L451VH543Q and L575M) may be useful to elucidate the role ofNrf2 in differential susceptibility to oxidative diseases

4 Oncogenic Somatic Mutations in HumanNF-E2-Related Factor 2

Somatic mutation is a change in the DNA of somatic cellsthat affects derived cells but is not inherited by offspringEfforts to discover somatic mutations have provided insightinto mutagenesis and cancer development Lung cancerparticularly non-small cell lung cancer (NSCLC) is theleading cause of cancer death worldwide Somatic mutationsof NRF2 and KEAP1 discovered in lung cancer patients havedetermined the oncogenic potential ofNRF2 [54 55] KEAP1somatic mutations were associated with its reduced proteinlevels in lung cancer tissues and cells [56 57] Investigationsof NSCLC in various ethnic populations as well as cancersin gastrointestine breast and prostate have coordinatelydemonstrated that multiple Cns somatic mutations in KEAP1cause dysfunction of the translated protein and in turnconstitutive activation of NRF2 increasing risk of neoplasiaand chemoresistance [12 55 58 59] Somatic mutations ofNRF2 have been detected in various cancer tissues (largelysquamous cell carcinomas) in Asian populations (Table 6)NRF2 mutations were significantly associated with NSCLCcases (squamous cell lung carcinoma adenocarcinoma) ofthe Japanese (107 [54]) the Chinese (23 [60]) andthe Koreans (8 [61]) as well as with lung cancer celllines Smoking history was also correlated with mutationoccurrence in all of the studies [54 60 61] In addition tolung cancers laryngeal squamous carcinoma (13 in [61])esophageal squamous cancer (ESC 22 in [60] 114 in[61]) head and neck cancers (25 in [54]) skin (117 casein [61]) and oral cancer cell lines had somatic changesin NRF2 In contrast to wide-spread KEAP1 mutationsmutations in NRF2 were clustered in DLGETGE motifs ofthe Neh2 domain which are critical in the ldquohinge and latchrdquomodel of KEAP1 binding [12] Similar to KEAP1 somaticmutations it has been postulated that NRF2 mutations incancer cells lead to NRF2 accumulation by suppressing itsubiquitination or KEAP1 binding which eventually confersmalignant potential and resistance to chemotherapy

Most variable sites in NRF2 included aa residues 29 (AspD) 31 (Gly G) 77 (Asp D) and 79 (Glu E) (Table 6)Residue 33 (Ser S) in the Neh2 domain is mutated by eithergenetic or somatic processes (Figure 4) Cns in the EDGFmotif of NRF2 was experimentally determined to impairrecognition of KEAP1 [54] NRF2 mutations were signif-icantly correlated with increased (25-fold) copy number(31 of mutants versus 3 wild types) in Japanese NSCLCcases [63] Aberrant mutation of NRF2 also led to increasedexpression of downstream effectors includingRagD known to


pL575M

pF71L

pH543QpL451V

pA151P pA151V pN159D pQ198delpV105D

pA204T pS224I225S226del pT253S pS278ApD305G

pM409V pR410HpP388L pA389G pT395I

Genomic DNA (reversed contig GRCm38 p1 C57BL6JNM 0109023)

Protein (NP 035032)1

51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001

g minus470gg minusg minus

c minus41c minus

c

c

c c

gg minus 6C

g minus125insTTC g minus118insC

g minus281delC

g minus63delCg minus1 (75704642 c minus234)

Translation start site (c +1)Termination codon (c +2025 +2027)

c minus136 minus134in-frame stop codonc minus8585

g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98

c minus197c minus209 minus202

gminus942 minus899 (cminus1175 minus1132) CpG islands [71]

g 460CgtT

g minus103CCgtT [51]

CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC

gminus826 minus654 (cminus1059 ) CpG islands [71]minus887

Figure 3 DNA (partial promoter and exons 1 and 5) and protein sequence ofmouseNrf2 SNPs and amino acid residues for non-synonymousSNPs are marked Promoter regions bearing 5CpG islands are underlined

151

201251301351401451501551601

Genetic mutation (Table 3 and Figure 2)Somatic mutation (Table 6)

Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151

Figure 4 Genetic and somatic mutation loci in human NRF2 protein


Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno

me(GI14933824975547698ndash75513576)SNPalleleand

geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)

51015840Flankingminus924

NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA

)51015840Flankingminus921

NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)

51015840Flankingminus913minus914

NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre

am(le75675512)sequences

asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE

-glutamicacidF-phenylalanineG

-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin

eQ-glutamineR-arginineS-serineT-threon

ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed


Table 6 NRF2 somatic mutations revealed in various human cancers

Domain Amino acid residues DNA mutation Cancer types (cases) ReferencesLocus Wild type Mutant

DLG motif

24 W (Trp) C (Cys) c72GgtCGgtT NSCLC neck ESC [54 62]K (Lys) c72TgtC ESC [62]

26 Q (Gln) E (Glu) c76CgtG NSCLC ESC [54 62]

27 D (Asp) G (Gly)lowast c80GgtA NSCLC [60]Y (Tyr) c79GgtT ESC [61]

28 I (Ile) T (Thr) c83CgtT NSCLC [54]

29 D (Asp) G (Gly) c86AgtG Head and neck ESC [54 62]H (His) c85GgtC NSCLC laynx [60 61]

30 L (Leu) F (Phe) c88CgtT NSCLC ESC [54 62]

31 G (Gly) A (Ala) c92GgtC NSCLC ESC skin [54 60ndash62]

32 V (Val) T (Thr) c95TgtG NSCLC [54]del c93 95delAGT ESC [61]

33ndash36 S-R-E-V S-R-E-V-S-R-E-Vlowast c97 108dupAGTCGAGCCGTA ESC [61]

34 R (Arg) Q (Gln) c101GgtA NCSCL [54 60 61]P (Pro) c101GgtC NSCLC [63]

ETGF motif

75 Q (Gln) H (His) c225AgtC Head and neck ESC [54 62]

77 D (Asp)

V (Val) c230AgtT NSCLC ESC [54 60 62]G (Gly) c230AgtG ESC [62]A (Ala) c230AgtC NSCLC [61]N (Asn) c229GgtA Larynx [61]

78 E (Glu) K (Lys) c232GgtA NSCLC ESC [54 62]

79 E (Glu)

K (Lys) c235GgtA NSCLC ESC [54 61 62]Q (Gln) c235GgtC NSCLC ESC [54 60ndash62]G (Gly) c236AgtG Larynx [61]E-E c234 236dupAGA ESC [61]

80 T (Thr) K (Lys) c239CgtACgtG NSCLC ESC [54 61 62]

80 T (Thr)P (Phe) c238AgtC ESC [62]I (Ile) c239CgtT Head and neck [54]A (Ala) c238AgtG NSCLC [63]

81 G (Gly) V (Val) c242GgtT ESC [61]D (Asp) c242GgtA NSCLC ESC [60ndash62]

82 E (Glu)

D (Asp) c246AgtT ESC oral cancer cell line [54 62]G (Gly) c245AgtG NSCLC [54]Q (Gln)lowast c244GgtC NSCLC ESC [60 61]V (Val)lowast c245AgtT ESC [61]

83 F (Phe) L (Leu)lowast c247TgtC NSCLC [60]NSCLC non-small cell lung cancer ESC esophageal squamous cancer and lowasterrors in reference fixed Number of cases 82 NSCLC and 10 ESC in [62] 125NSCLC 70 ESC 23 larynx and 17 skin in [61] 103 NSCLC and 12 head and neck in [54] 90 NSCLC in [63] 103 NSCLC in [60]

be involved in squamous lung cancer cell proliferation [64]suggesting that the mutation is functional and overcomesKEAP1 inhibition Singh et al [65] determined in vitrothat RNAi-mediated depletion of NRF2 in lung cancer cellsenhanced ROS production and susceptibility to cell deathby ionizing radiation These studies support the concept thatelevated NRF2 and ARE responsiveness provides cancer cellswith proliferative advantage for malignant transformation

and undue protection from anti-cancer therapy Onco-genic epidermal growth factor receptor (EGFR) signaling isrecently found to be critical in NRF2-mediated proliferationof NSCLC cells [66]

Collectively ldquogain of functionrdquo mutations in NRF2 thatreduce KEAP1 recognition are suggested to be predictivemarkers for poor responsiveness to chemotherapy and radi-ation therapy Although NRF2-mediated cellular defense


processes are essential in the initiation stage enhancedNRF2-ARE activity in advanced stages of cancer developmentmay create a favorable intracellular environment for tumorcell growth and survival [67 68] In this context NRF2may be a potential molecular target for the treatment ofradio-resistance cancers especially those that have ldquoloss offunctionrdquo mutations in EGFR KRAS or KEAP1 as well asldquogain of functionrdquo mutations in NRF2

5 Epigenetic Alterations of NF-E2-RelatedFactor 2

Epigenetic modifications are alterations of molecules inter-acting with genes without changes to the primary DNAsequence They include post-translational modification ofhistones DNA methylation events chromatin conforma-tional changes and alterations to noncoding regulatoryRNAs Epigenetic alterations are stable and often inheritablebut are reversible and may affect expression of the geneDysregulation or defects in epigenetic processes particularlyhypermethylation of tumor suppressor gene promoters (egCpG islands) or histone modifications are thought to beassociated with carcinogenesis Investigators have reportedhypermethylation in CpG islands of KEAP1 which wereassociated with reduced KEAP1 expression in human cancersfrom lung prostate colon and so forth [69ndash72] Similar tosomatic mutations epigenetic changes on KEAP1 impairedthe function of its encoded protein leading to constitutiveNRF2 activation

Supporting the role of ldquopathogenic mutationsrdquo in NRF2expression of Nrf2 and downstream Nqo1 was suppressedin prostate tumors of mice (transgenic adenocarcinomaof mouse prostate TRAMP) Among 15 promoter CpGislands located between minus942 and minus654 (cminus1175 cminus1132and cminus1059 cminus887 gap in cminus1131 cminus1060 see Figure 3)hypermethylation of the first 5 CpG islands (minus942 minus899 andcminus1175 cminus1132) was significantly associated with tumorige-nesis [73] Moreover treatment with inhibitors for DNAmethyltransferase and histone deacetylase restored Nrf2expression in these tumor cells [73] A dietary phytochemicalcurcumin known as a DNA hypomethylation agent restoredepigenetically silent Nrf2 expression through CpG demethy-lation in carcinogen-induced mouse tumor cells [74]

The whole genome epigenetic datasets for 5 species arepublicly accessible at NCBI Epigenomics [75 76]The humanNRF2 epigenome of primary cells (breast penis) and H1stem cell line as well as mouse Nrf2 CpG island methylationdata for sperm blood and cerebellum are currently avail-able (httpwwwncbinlmnihgovepigenomics) Althoughno direct evidence of disease-associated epigenetic modu-lation has been identified in human NRF2 various phyto-chemical NRF2 agonists such as sulforaphane and curcuminhave shown their roles in DNA methylation and histonemodification (see reviews by Lee and colleagues eg [77])Taken together epigenetic modifications of theNRF2KEAP1axle are predicted to cause dysregulation of ARE-mediatedcellular defense leading to deleterious health effects and

phytochemical antioxidants as epigenetic modulators forNRF2 are suggested to be useful in cancer prevention

6 Conclusions

NRF2 is evolutionally conserved with high-sequence homol-ogy in many species However it is a highly mutable geneand numerous genetic variants have been discovered inhuman ethnic groups Importantly certain SNPs or haplo-types have been identified in various diseases as ldquoat-riskrdquoalleles and are related to functional alterations In additionto genetic variations multiple somatic mutations identifiedin the KEAP1 recognition domain of NRF2 in cancer cellshave been found to be oncogenic due to dysregulation ofNRF2 homeostasis by its excess ldquogain of functionrdquo Epigeneticalteration of theNRF2 is under investigation and is predictedto have pathogenic influences as learned from mouse andphytochemical agonist studies Continuous updates of Nrf2allelic variants in inbred mouse strains will provide a usefultool for effective experimental designs formodels of oxidativedisorders to provide insight into the disease mechanisms andintervention strategies

Abbreviations

AD Alzheimerrsquos diseaseALI acute lung injuryARE antioxidant response elementbZIP basic leucine zippercds coding DNA sequencesCI confidence intervalCOPD chronic obstructive pulmonary diseaseESC esophageal squamous cancerFEV1 forced expiratory volume in one second

Gbp giga base pairsGST glutathione S-transferaseGWAS genome-wide association studyHGVS Human Genome Variation SocietyHO-1 heme oxygenase-1119867 119901119910119897119900119903119894 119867119890119897119894119888119900119887119886119888119905119890119903 119901119910119897119900119903119894KEAP1 Kelch-like ECH activating protein 1MPD Mouse Phenome DatabaseMRP multidrug resistance proteinNCBI National Center for Biotechnology InformationNeh NRF2-ECH homologyNfe2l2 nuclear factor (erythroid-derived 2)-like 2Nrf2 NF-E2-related factor 2NSCLC nonsmall cell lung cancerNQO1 NAD(P)Hquinone oxidoreductase 1OR odds ratioPD Parkinsonrsquos diseasePM particulate matterROS reactive oxygen speciesSLE systemic lupus erythematosusSNP single nucleotide polymorphismSOD superoxide dismutaseURT untranslated region


Disclosure

Authorrsquos contribution to the Work was done as part of theAuthorrsquos official duties as a NIH employee and is a Work ofthe United States Government Therefore copyright may notbe established in the United States

Conflict of Interests

The author declares that there is no conflict of interests

Acknowledgments

The research related to this paper was supported by theIntramural Research Program of the National Institutes ofHealth of the National Institute of Environmental HealthSciences (NIEHS) Drs Steven Kleeberger and StephanieLondon at the NIEHS provided excellent critical review ofthis paper The author thanks Mrs Jacqui Marzec for herhelpful comments and English editing

References

[1] J Y Chan M C Cheung P Moi K Chan and Y W KanldquoChromosomal localization of the humanNF-E2 family of bZIPtranscription factors by fluorescence in situ hybridizationrdquoHuman Genetics vol 95 no 3 pp 265ndash269 1995

[2] K Itoh K Igarashi N Hayashi M Nishizawa and MYamamoto ldquoCloning and characterization of a novel erythroidcell-derived CNC family transcription factor heterodimerizingwith the small Maf family proteinsrdquo Molecular and CellularBiology vol 15 no 8 pp 4184ndash4193 1995

[3] W O Osburn and T W Kensler ldquoNRF2 signaling an adaptiveresponse pathway for protection against environmental toxicinsultsrdquoMutation Research vol 659 no 1-2 pp 31ndash39 2008

[4] D Papp K Lenti D Modos D Fazekas Z Dul D Tureiet al ldquoThe NRF2-related interactome and regulome containmultifunctional proteins and fine-tuned autoregulatory loopsrdquoFEBS Letters vol 586 no 13 pp 1795ndash1802 2012

[5] X Wang D J Tomso B N Chorley et al ldquoIdentificationof polymorphic antioxidant response elements in the humangenomerdquo Human Molecular Genetics vol 16 no 10 pp 1188ndash1200 2007

[6] D Malhotra E Portales-Casamar A Singh et al ldquoGlobalmapping of binding sites for NRF2 identifies novel targets incell survival response through ChIP-Seq profiling and networkanalysisrdquo Nucleic Acids Research vol 38 no 17 pp 5718ndash57342010

[7] K Chan R Lu J C Chang and Y W Kan ldquoNRF2 a memberof the NFE2 family of transcription factors is not essential formurine erythropoiesis growth and developmentrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 93 no 24 pp 13943ndash13948 1996

[8] K Itoh T Chiba S Takahashi et al ldquoAn NRF2small Mafheterodimer mediates the induction of phase II detoxifyingenzyme genes through antioxidant response elementsrdquo Bio-chemical and Biophysical Research Communications vol 236no 2 pp 313ndash322 1997

[9] FMartin J M vanDeursen R A Shivdasani CW Jackson AG Troutman and P A Ney ldquoErythroid maturation and globin

gene expression inmicewith combined deficiency ofNF-E2 andNrf-2rdquo Blood vol 91 no 9 pp 3459ndash3466 1998

[10] K Itoh N Wakabayashi Y Katoh et al ldquoKEAP1 repressesnuclear activation of antioxidant responsive elements by NRF2through binding to the amino-terminal Neh2 domainrdquo Genesand Development vol 13 no 1 pp 76ndash86 1999

[11] A Kobayashi M I Kang H Okawa et al ldquoOxidative stresssensor KEAP1 functions as an adaptor for Cul3-based E3 ligaseto regulate proteasomal degradation of NRF2rdquo Molecular andCellular Biology vol 24 no 16 pp 7130ndash7139 2004

[12] K Taguchi H Motohashi and M Yamamoto ldquoMolecularmechanisms of the KEAP1-NRF2 pathway in stress responseand cancer evolutionrdquo Genes to Cells vol 16 no 2 pp 123ndash1402011

[13] K Mukaigasa L T Nguyen L Li H Nakajima M Yamamotoand M Kobayashi ldquoGenetic evidence of an evolutionarilyconserved role for NRF2 in the protection against oxidativestressrdquoMolecular and Cellular Biology vol 32 no 21 pp 4455ndash4461 2012

[14] JMaher andMYamamoto ldquoThe rise of antioxidant signalingmdashthe evolution and hormetic actions of NRF2rdquo Toxicology andApplied Pharmacology vol 244 no 1 pp 4ndash15 2010

[15] S C Lo X Li M T Henzl L J Beamer and M HanninkldquoStructure of the KEAP1NRF2 interface provides mechanisticinsight intoNRF2 signalingrdquoThe EMBO Journal vol 25 no 15pp 3605ndash3617 2006

[16] V A McKusick ldquoMendelian inheritance in man and its onlineversion OMIMrdquo American Journal of Human Genetics vol 80no 4 pp 588ndash604 2007

[17] B Yalcin D J Adams J Flint and T M Keane ldquoNext-generation sequencing of experimental mouse strainsrdquo Mam-malian Genome vol 23 no 9-10 pp 490ndash498 2012

[18] D R Bentley S Balasubramanian H P Swerdlow et alldquoAccurate whole human genome sequencing using reversibleterminator chemistryrdquo Nature vol 456 no 7218 pp 53ndash592008

[19] P S G Chain D V Grafham R S Fulton et al ldquoGenomeproject standards in a new era of sequencingrdquo Science vol 326no 5950 pp 236ndash237 2009

[20] RHWaterstonK Lindblad-Toh E Birney J Rogers J F AbrilP Agarwal et al ldquoInitial sequencing and comparative analysis ofthe mouse genomerdquo Nature vol 420 pp 520ndash562 2002

[21] T M Keane L Goodstadt P Danecek M A White K WongB Yalcin et al ldquoMouse genomic variation and its effect onphenotypes and gene regulationrdquoNature vol 477 pp 289ndash2942011

[22] T Yamamoto K Yoh A Kobayashi et al ldquoIdentification ofpolymorphisms in the promoter region of the human NRF2generdquo Biochemical and Biophysical Research Communicationsvol 321 no 1 pp 72ndash79 2004

[23] J M Marzec J D Christie S P Reddy et al ldquoFunctionalpolymorphisms in the transcription factor NRF2 in humansincrease the risk of acute lung injuryrdquo The FASEB Journal vol21 no 9 pp 2237ndash2246 2007

[24] H Fukushima-Uesaka Y Saito K Maekawa et al ldquoGeneticvariations and haplotype structures of transcriptional factorNRF2 and its cytosolic reservoir protein KEAP1 in JapaneserdquoDrug Metabolism and Pharmacokinetics vol 22 no 3 pp 212ndash219 2007

[25] E J Cordova R Velazquez-Cruz F Centeno V Baca and LOrozco ldquoThe NRF2 gene variant -653GA is associated with


nephritis in childhood-onset systemic lupus erythematosusrdquoLupus vol 19 no 10 pp 1237ndash1242 2010

[26] M von Otter S Landgren S Nilsson et al ldquoAssociation ofNRF2-encoding NFE2L2 haplotypes with Parkinsonrsquos diseaserdquoBMCMedical Genetics vol 11 no 1 article 36 2010

[27] JMHartikainenM TengstromVMKosmaV L Kinnula AMannermaa andY Soini ldquoGenetic polymorphisms and proteinexpression of NRF2 and sulfiredoxin predict survival outcomesin breast cancerrdquo Cancer Research vol 72 pp 5537ndash5546 2012

[28] T Arisawa T Tahara T Shibata et al ldquoThe relationshipbetween Helicobacter pylori infection and promoter polymor-phism of the NRF2 gene in chronic gastritisrdquo InternationalJournal of Molecular Medicine vol 19 no 1 pp 143ndash148 2007

[29] T Arisawa T Tahara T Shibata et al ldquoThe influence ofpromoter polymorphism of nuclear factor-erythroid 2-relatedfactor 2 gene on the aberrant DNA methylation in gastricepitheliumrdquo Oncology Reports vol 19 no 1 pp 211ndash216 2008

[30] T Arisawa T Tahara T Shibata et al ldquoNRF2 gene pro-moter polymorphism and gastric carcinogenesisrdquo Hepato-Gastroenterology vol 55 no 82-83 pp 750ndash754 2008

[31] T Arisawa T Tahara T Shibata et al ldquoNRF2 gene promoterpolymorphism is associated with ulcerative colitis in a Japanesepopulationrdquo Hepato-Gastroenterology vol 55 no 82-83 pp394ndash397 2008

[32] C C Hua L C Chang J C Tseng C M Chu Y C Liu andW B Shieh ldquoFunctional haplotypes in the promoter region oftranscription factor NRF2 in chronic obstructive pulmonarydiseaserdquo Disease Markers vol 28 no 3 pp 185ndash193 2010

[33] S O Shaheen R B Newson S M Ring M J Rose-ZerilliJ W Holloway and A J Henderson ldquoPrenatal and infantacetaminophen exposure antioxidant gene polymorphismsand childhood asthmardquo The Journal of Allergy and ClinicalImmunology vol 126 no 6 pp 1141e7ndash1148e7 2010

[34] H Masuko T Sakamoto Y Kaneko et al ldquoLower FEV1 innon-COPD nonasthmatic subjects association with smokingannual decline in FEV1 total IgE levels and TSLP genotypesrdquoInternational Journal of Chronic Obstructive Pulmonary Diseasevol 6 pp 181ndash189 2011

[35] C P Guan M N Zhou A E Xu et al ldquoThe susceptibilityto vitiligo is associated with NF-E2-related factor 2 (NRF2)gene polymorphisms a study on Chinese Han populationrdquoExperimental Dermatology vol 17 no 12 pp 1059ndash1062 2008

[36] J Bouligand O Cabaret M Canonico et al ldquoEffect of NFE2L2genetic polymorphism on the association between oral estrogentherapy and the risk of venous thromboembolism in post-menopausal womenrdquo Clinical Pharmacology amp Therapeuticsvol 89 no 1 pp 60ndash64 2011

[37] D S OrsquoMahony B J Glavan T D Holden C Fong R A BlackG Rona et al ldquoInflammation and immune-related candidategene associations with acute lung injury susceptibility andseverity a validation studyrdquo PLoS ONE vol 7 no 12 Article IDe51104 2012

[38] I Ungvari E Hadadi V Virag et al ldquoRelationship between airpollutionNFE2L2 gene polymorphisms and childhood asthmain aHungarian populationrdquo Journal of CommunityGenetics vol3 no 1 pp 25ndash33 2012

[39] M SiedlinskiD S Postma JMA Boer et al ldquoLevel and courseof FEV1 in relation to polymorphisms inNFE2L2 andKEAP1 inthe general populationrdquo Respiratory Research vol 10 article 732009

[40] C C Hong C B Ambrosone J Ahn et al ldquoGenetic variabilityin iron-related oxidative stress pathways (NRF2 NQ01 NOS3

and HO-1) iron intake and risk of postmenopausal breastcancerrdquo Cancer Epidemiology Biomarkers and Prevention vol16 no 9 pp 1784ndash1794 2007

[41] C Canova C Dunster F J Kelly C Minelli P L Shah CCaneja et al ldquoPM10-induced hospital admissions for asthmaand chronic obstructive pulmonary disease the modifyingeffect of individual characteristicsrdquo Epidemiology vol 23 no 4pp 607ndash615 2012

[42] A J Henderson R B Newson M Rose-Zerilli S M RingJ W Holloway and S O Shaheen ldquoMaternal NRF2 andgluthathione-S-transferase polymorphisms donotmodify asso-ciations of prenatal tobacco smoke exposure with asthma andlung function in school-aged childrenrdquo Thorax vol 65 no 10pp 897ndash902 2010

[43] C Xing A L Sestak J A Kelly et al ldquoLocalization andreplication of the systemic lupus erythematosus linkage signalat 4p16 interaction with 2p11 12q24 and 19q13 in EuropeanAmericansrdquo Human Genetics vol 120 no 5 pp 623ndash631 2007

[44] T F Wong K Yoshinaga Y Monma K Ito H NiikuraS Nagase et al ldquoAssociation of KEAP1 and NRF2 geneticmutations and polymorphisms with endometrioid endometrialadenocarcinoma survivalrdquo International Journal of Gynecologi-cal Cancer vol 21 no 8 pp 1428ndash1435 2011

[45] M von Otter S Landgren S Nilsson et al ldquoNRF2-encodingNFE2L2 haplotypes influence disease progression but not riskin Alzheimerrsquos disease and age-related cataractrdquoMechanisms ofAgeing and Development vol 131 no 2 pp 105ndash110 2010

[46] S Tsang Z Sun B Luke et al ldquoA comprehensive SNP-basedgenetic analysis of inbred mouse strainsrdquoMammalian Genomevol 16 no 7 pp 476ndash480 2005

[47] C M Wade E J Kulbokas III A W Kirby et al ldquoThe mosaicstructure of variation in the laboratory mouse genomerdquoNaturevol 420 no 6915 pp 574ndash578 2002

[48] T Wiltshire M T Pletcher S Batalov et al ldquoGenome-widesingle-nucleotide polymorphism analysis defines haplotypepatterns in mouserdquo Proceedings of the National Academy ofSciences of the United States of America vol 100 no 6 pp 3380ndash3385 2003

[49] K A Frazer E Eskin H M Kang et al ldquoA sequence-basedvariation map of 827 million SNPs in inbred mouse strainsrdquoNature vol 448 no 7157 pp 1050ndash1053 2007

[50] T P Maddatu S C Grubb C J Bult andM A Bogue ldquoMousephenome database (MPD)rdquo Nucleic Acids Research vol 40 ppD887ndashD894 2007

[51] A Kirby H M Kang C M Wade et al ldquoFine mapping in 94inbred mouse strains using a high-density haplotype resourcerdquoGenetics vol 185 no 3 pp 1081ndash1095 2010

[52] H Y Cho A E Jedlicka S P M Reddy L Y Zhang T WKensler and S R Kleeberger ldquoLinkage analysis of susceptibilityto hyperoxia NRF2 is a candidate generdquo American Journal ofRespiratory Cell and Molecular Biology vol 26 no 1 pp 42ndash512002

[53] H Y Cho A E Jedlicka S P M Reddy et al ldquoRole of NRF2in protection against hyperoxic lung injury in micerdquo AmericanJournal of Respiratory Cell and Molecular Biology vol 26 no 2pp 175ndash182 2002

[54] T Shibata T Ohta K I Tong et al ldquoCancer related mutationsin NRF2 impair its recognition by KEAP1-Cul3 E3 ligase andpromote malignancyrdquo Proceedings of the National Academy ofSciences of the United States of America vol 105 no 36 pp13568ndash13573 2008


[55] A Singh V Misra R K Thimmulappa et al ldquoDysfunctionalKEAP1-NRF2 interaction in non-small-cell lung cancerrdquo PLoSMedicine vol 3 no 10 article e420 2006

[56] T Ohta K Iijima M Miyamoto et al ldquoLoss of KEAP1 functionactivates NRF2 and provides advantages for lung cancer cellgrowthrdquo Cancer Research vol 68 no 5 pp 1303ndash1309 2008

[57] B Padmanabhan K I Tong T Ohta et al ldquoStructural basisfor defects of KEAP1 activity provoked by its point mutationsin lung cancerrdquoMolecular Cell vol 21 no 5 pp 689ndash700 2006

[58] T Shibata A Kokubu M Gotoh et al ldquoGenetic alteration ofKEAP1 confers constitutive NRF2 activation and resistance tochemotherapy in gallbladder cancerrdquoGastroenterology vol 135no 4 pp 1358e4ndash1368e4 2008

[59] N J Yoo H R Kim Y R Kim C H An and S H LeeldquoSomatic mutations of the KEAP1 gene in common solidcancersrdquo Histopathology vol 60 no 6 pp 943ndash952 2012

[60] Y Hu Y Ju D Lin Z Wang Y Huang S Zhang et alldquoMutation of the NRF2 gene in non-small cell lung cancerrdquoMolecular Biology Reports vol 39 no 4 pp 4743ndash4747 2012

[61] Y R Kim J EOhM S Kim et al ldquoOncogenicNRF2mutationsin squamous cell carcinomas of oesophagus and skinrdquo TheJournal of Pathology vol 220 no 4 pp 446ndash451 2010

[62] T Shibata A Kokubu S Saito et al ldquoNRF2 mutation confersmalignant potential and resistance to chemoradiation therapyin advanced esophageal squamous cancerrdquo Neoplasia vol 13pp 864ndash873 2011

[63] H Sasaki M Shitara K Yokota Y Hikosaka S MoriyamaM Yano et al ldquoIncreased NRF2 gene (NFE2L2) copy numbercorrelates with mutations in lung squamous cell carcinomasrdquoMolecular Medicine Reports vol 6 no 2 pp 391ndash394 2012

[64] H Sasaki M Shitara K Yokota Y Hikosaka S Moriyama MYano et al ldquoRagD gene expression andNRF2mutations in lungsquamous cell carcinomasrdquo Oncology Letters vol 4 pp 1167ndash1170 2012

[65] A Singh M Bodas N Wakabayashi F Bunz and S BiswalldquoGain of NRF2 function in non-small-cell lung cancer cellsconfers radioresistancerdquo Antioxidants and Redox Signaling vol13 no 11 pp 1627ndash1637 2010

[66] T Yamadori Y Ishii SHommaYMorishimaKKurishimaKItoh et al ldquoMolecular mechanisms for the regulation of NRF2-mediated cell proliferation in non-small-cell lung cancersrdquoOncogene vol 31 pp 4768ndash4777 2012

[67] A K Bauer H Y Cho L Miller-Degraff C Walker K HelmsJ Fostel et al ldquoTargeted deletion of NRF2 reduces urethane-induced lung tumor development in micerdquo PLoS ONE vol 6no 10 Article ID e26590 2011

[68] H Y Cho and S R Kleeberger ldquoNRF2 protects against airwaydisordersrdquo Toxicology and Applied Pharmacology vol 244 no1 pp 43ndash56 2010

[69] R Wang J An F Ji H Jiao H Sun and D Zhou ldquoHyperme-thylation of the KEAP1 gene in human lung cancer cell linesand lung cancer tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 373 no 1 pp 151ndash154 2008

[70] P Zhang A Singh S Yegnasubramanian et al ldquoLoss ofkelch-like ECH-associated protein 1 function in prostate cancercells causes chemoresistance and radioresistance and promotestumor growthrdquoMolecular Cancer Therapeutics vol 9 no 2 pp336ndash346 2010

[71] N Hanada T Takahata Q Zhou et al ldquoMethylation of theKEAP1 gene promoter region in human colorectal cancerrdquoBMCCancer vol 12 article 66 2012

[72] L A Muscarella R Barbano V DrsquoAngelo et al ldquoRegulationof KEAP1 expression by promoter methylation in malignantgliomas and association with patientrsquos outcomerdquo Epigeneticsvol 6 no 3 pp 317ndash325 2011

[73] S Yu T O Khor K L Cheung et al ldquoNRF2 expressionis regulated by epigenetic mechanisms in prostate cancer ofTRAMP micerdquo PLoS ONE vol 5 no 1 Article ID e8579 2010

[74] T O Khor Y Huang T Y Wu L Shu J Lee and A N KongldquoPharmacodynamics of curcumin as DNA hypomethylationagent in restoring the expression of NRF2 via promoter CpGsdemethylationrdquo Biochemical Pharmacology vol 82 no 9 pp1073ndash1078 2011

[75] I M Fingerman L McDaniel X Zhang et al ldquoNCBI epige-nomics a new public resource for exploring epigenomic datasetsrdquo Nucleic Acids Research vol 39 supplemen 1 pp D908ndashD912 2011

[76] I M Fingerman X Zhang W Ratzat N Husain R F Cohenand G D Schuler ldquoNCBI epigenomics whatrsquos new for 2013rdquoNucleic Acids Research vol 41 no 1 pp D221ndashD225 2013

[77] J H Lee T O Khor L Shu Z Y Su F Fuentes andA N Kong ldquoDietary phytochemicals and cancer preventionNRF2 signaling epigenetics and cell death mechanisms inblocking cancer initiation and progressionrdquo Pharmacology ampTherapeutics vol 137 no 2 pp 153ndash171 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2013

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawi Publishing Corporation httpwwwhindawicom Volume 2013

The Scientific World Journal

International Journal of

EndocrinologyHindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch


OphthalmologyJournal of


ISRN Allergy


BioMed Research International


ObesityJournal of


ISRN Addiction



Computational and Mathematical Methods in Medicine

ISRN AIDS


Clinical ampDevelopmentalImmunology

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2013

Diabetes ResearchJournal of


Evidence-Based Complementary and Alternative Medicine

Volume 2013Hindawi Publishing Corporationhttpwwwhindawicom


Gastroenterology Research and Practice


ISRN Biomarkers


MEDIATORSINFLAMMATION

of


Carcinogenesis

Mammary carcinoma (+)Urinary bladder carcinogenesis (+)

Skin tumor (+)

Kidney and bladder

Diabetic nephropathy (+)As toxicity (+)

Brain and neuromuscular systemIschemic brain injury (+)

Cerebral ischemia and stroke (+)Hearing loss and ototoxicity (+)

AirwaysAcute lung injury (+)COPDemphysema (+)Allergy and asthma (+)Pulmonary fibrosis (+)

Steroid resistance (+)

Inflammationimmunity and developmentSepsis (+)Autoimmune encephalomyelitis (+)Rheumatoid arthritis and cartilage destruction (+)

Heart and circulation

Hemolytic anemia (+)

MetabolismLipid homeostasis (+)

Glucose homeostasis (+)

Skin and eyeSkin healing (+)

Uveitis (+)

GastrointestineAlcoholic liver injury (+)

Acetaminophen hepatotoxicity (+)Bile acid homeostasis (+)

Colitis (+)

Various xenobiotic toxicity (+)Cholestatic liver injury (+)

Steatohepatitis (+)Gastroparesis (+)Liver fibrosis (+)

Acute intestinal mucosal injury (+)

Traumatic brain injury (+)

Spinal cord injury complications (+)

Brain leukoencephalopathy with astrogliosis (+)Gliosis and dopaminergic nigrostriatal degeneration (+)Intracerebral hemorrhage-induced brain injury (+)

Cardiac hypertrophy (+)

Ischemia-induced neovascularization (+)Atherosclerosis (minus)

Lupus-like autoimmune nephritis (+)Spermatogenesis (+)

Gastric neoplasia (+)Colorectal cancer (+)

Lung adenomas (minus)

Pseudomonas aeruginosa infection (+)

Bronchopulmonary displasia (+)Respiratory syncytial virus disease (+)

High-fat-diet induced obesity (+)

UV-induced skin aging (+)

Retinal ischemia-reperfusion (+)Retinopathy of prematurity (+)

Ischemic nephrotoxicity (+)Cisplatin nephrotoxicity (+)

Pollutant (diesel exhaust O3) toxicity (+)

Parkinsonrsquos disease (+)

Nrf 2

Cardiomyocyte damage (+)

Figure 1 Role of Nrf2 in human pathogenesis learned from model studies using mice genetically deficient in Nrf2 (+) indicates protectiveor beneficial effects and (minus) indicates aberrant roles

NRF2 [11]) However modifications of KEAP1 (eg cysteineresidues) and NRF2 (eg serine residues) under stressedconditions activate NRF2 by liberating it from a ldquohinge andlatchrdquo NRF2-KEAP1 affinity binding allowing its nucleartranslocation [12]

In the current review I address genetic aspects of humanNRF2 and its homologs in other vertebrate species Sequencevariations in humanNRF2 andmurineNrf2 including single-nucleotide polymorphisms (SNPs)were collected frompublicdatabases and compiled Mutations that have been associatedwith disease risks are defined Nongenetic variations includ-ing somatic mutations and epigenetic modifications are alsodescribed Although the current review does not deal withmutations in other species recent characterization of nrf2mutant zebrafishwhichwere hypersensitive to environmentaltoxicants [13] also provides a useful investigational tool

2 Sequence of NF-E2-Related Factor 2and Cross-Species Homology

Homology scores of gene (coding DNA sequences cds) andprotein across 10 species were compared with human NRF2The highest sequence homology (98-99) was with chim-panzee and rhesus monkey while the lowest similarity wasfound with zebrafish (Table 1) While there is approximately

about 83 homology in cds and protein sequences of humansand rodents 51015840-untranslated regions (51015840-UTR UTR-5) ofthese strains extend differentially (114 bp in human 233 bp inmouse and 82 bp in rat) and the human 51015840-UTR does notshare significant sequence homology with either rat ormouse(the rat is 94 homologous with the 31015840 portion of mouse 51015840-UTR)

Human NRF2 is located in the cytogenetic band 2q312of chromosome 2 spanning 178095031ndash178129859 bp as acomplementary sequence (gene ID 4780 Table 1) MurineNrf2 maps as a complementary sequence to chromosome2 C3 (4475 centimorgan) and spans 75675519ndash75704641(gene ID 18024 Table 1) The complete cds of NRF2 is2859 bp and there are 14 transcript variants reported(httpuseastensemblorgHomo sapiens) Mouse Nrf2mRNA spans 2469 bp and another variant has been re-ported (httpuseastensemblorgMus musculus) The hu-man NRF2 protein (ID NP 006155) contains 605 amino acid(aa) residues with molecular weight of 677 kDa (isoform1) and total 12 isoforms are published (the National Centerfor Biotechnology Information NCBI httpwwwncbinlmnihgovrefseqrsg eEnsemble httpuseastensemblorgindexhtml UniProt Consortium httpwwwuniprotorguniprotQ16236 httpwwwuniprotorguniprotQ60795)Mouse Nrf2 protein (ID NP 035032) comprises 597 aa at668 kDa (Table 1) Structurally there are 6 NRF2-ECH


Table1Geneo

rtho

logy

ofNF-E2

-related

factor

2acrossthes

pecies

Species

Hum

anHom

osapiens

Cat

Felis

catus

Chim

panzee

Pantro

glodytes

Dog

Canislupus

familiaris

Cattle

Bostaurus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdashGenes

ynon

yms

NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2Ch

romosom

emap

2q312

C12B

362

Genom

esequence

(NCB

IBuild)

NC

0000

0211

(GRC

h37p

10)

NC

1087301

(Feliscatus-62)

NC

0064703

(Pan

troglod

ytes-214)

NC

0066183

(CanFam31)

AC00

01591

(Bos

taurus

UMD

31)

Prim

arysource

HGNC

7782

mdashmdash

mdashBO

S1716

GeneID

mapping

(orie

ntationlowast

)

4780

178095031minus178129859(minus)

1010

9881

2165356974minus

165392728(minus)

7426

22181721941minus181756837(minus)

4788

1320989206minus21021893

(minus)

4970

2419659540minus19692048

Ensembleg

eneID

(mapping

)EN

SG00

00011604

4(178092323minus178257425)

mdashEN

SPTR

G00

000012677

(181721949minus181756285)

ENSC

AFG

0000

0013506

(20987569minus

21022230)

ENSB

TAG00

000019255

(19659540minus19692048)

RefSeq

IDm

RNA

size

NM

006164

4(G

I372620346)2859b

p

XM0039908931

(GI410968909)

predicted2394

bp

XM00114

58762


2850

bp

XM5359753

(GI345797173)

predicted2570

bp

NM

0010116

782

(GI147904941)240

9bp

ProteinID

(aaMW

sect )NP00

61552

(60567696)

XP0039909421

(60667797)

XP00114

58762

(60567686)

XP5359751

(60167087)

NP0010116

782

(60767813)

UniProt

IDQ16236

mdashA2T

6Y9

mdashQ5N

UA62

Varia

nts

14transcrip

ts12

isoform

s3transcrip

ts3iso

form

s5transcrip

ts5iso

form

s2transcrip

ts2iso

form

smdash

Hom

olog

ygeneprotein

100100

893914

999999

893888

905891


Table1Con

tinued

Species

Rhesus

mon

key

Macacamulatta

Chicken

Gallusgallus

Zebrafish

Daniorerio

Mou

seMus

musculus

Rat

Rattu

snorvegicus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2nu

clear


2lik

e2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdash

Genes

ynon

yms

NFE

2L2NRF

2Mmu966

NFE

2L2NRF

2nfe2l2N

rf2N

rf2a

wufc15g09wufj6

7e03

Nfe2

l2N

rf2A

I194320

Nfe2

l2N

rf2

Chromosom

emap

127

92C

3(4475

cM)

3q23

Genom

esequence

(NCB

IBuild)

NC

0078691

NC

0060

943

NC

0071205

(Zv9)

NC

0000

687

(GRC

m38p1)

NC

0051023

(Rno

r50)

Prim

arySource

mdashCG

NC

4960

4ZF

INZ

DB-GEN

E-030723-2

MGI108420

RGD620360

GeneIDmapping

(orie

ntationlowast

)70

7606

40848940minus40

8846

00(minus)

3960

1415304546minus15320356

3601

491643746minus

1670288

1802

475675519minus757046

41(minus)

8361

969041647minus69069070

(minus)

Ensembleg

eneID

(mapping

)EN

SMMUG00

0000

01861

(40848948minus

40884174)

ENSG

ALG

0000

0009240

(16897956minus

16922637)

ENSD

ARG

0000

0042824

(1643631minus1672715)

ENSM

USG

0000

0015839

(75675513minus

757046

41)

ENSR

NOG00

0000

01548

(58366

693minus

58394118)

RefSeq

IDm

RNA

size

NM

0012576071

(GI383872375)2335b

pNM

2051171

(GI45384113)2555

bpNM

1828891

(GI33504557)2149

bpNM

0109023

(GI76573877)2469

bpNM

0317892

(GI402692377)2305b

pProteinID

(aaMW

sect )NP001244

5361

(606

67703)

NP9904

481

(58265160)

NP8783091

(58665757)

NP0350321

(59766770)

NP1139771

(59766825)

UniProt

IDF7GPD

8Q90834

Q8JIM

1Q60795

O54968

Varia

nts

2transcrip

ts2iso

form


1transcript1isoform

1transcript

1transcript1isoform

Hom

olog

ygeneprotein

988990

726674

546491

834825

838832

Referto

httpwwwncbinlm

nihgovhom

ologene2412

and

reference


molog

yDetails

ofho

molog

yscores

and

sequ

encescan

bealso

obtained

byblastagainsthu

man

sequ

ence

(http

blastn

cbin

lmnihgov)

Furtherinform

ation

ontranscrip

tvaria

ntsand

protein

isoform

sareview

able

bygene

IDat

NCB

I(http

wwwncbinlm

nihgovrefseqrsg)

and

eEn

semble

(http

useastensembleo

rgin

dexhtml)or

byproteinID

atUniProt(http

wwwun

iproto

rg)

sect MWpredicted

molecularweightfrom

NCB

I(MW

inUniProtvarie

sslightly)Re

fSeqreference

sequ

enceaaam

ino

acidsandlowastgene

incomplem

ento

rientation




Neh216ndash89





(Keap1-independent)

Neh1435ndash568















minus400

minus500

minus50minus100

minus200

minus300

minus450

minus350

minus250

minus150

g minus

g


pV268M

pR517K pH453L



51101151201251301351401451501551601





151

101151201251301351401451501551601

2351


old + 1 [22]

g minus1 (178130354)

c minus96delC




p R43Q p R43W



c 9minus95

g minus178

c minus304

c 8minus13

c 2minus16

TgtA

CgtT

GgtA

GgtA

GgtA

GgtT

GgtCAgtG

AgtCAgtG



4versus GCC

5







inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table1Geneo

rtho

logy

ofNF-E2

-related

factor

2acrossthes

pecies

Species

Hum

anHom

osapiens

Cat

Felis

catus

Chim

panzee

Pantro

glodytes

Dog

Canislupus

familiaris

Cattle

Bostaurus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdashGenes

ynon

yms

NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2NFE

2L2NRF

2Ch

romosom

emap

2q312

C12B

362

Genom

esequence

(NCB

IBuild)

NC

0000

0211

(GRC

h37p

10)

NC

1087301

(Feliscatus-62)

NC

0064703

(Pan

troglod

ytes-214)

NC

0066183

(CanFam31)

AC00

01591

(Bos

taurus

UMD

31)

Prim

arysource

HGNC

7782

mdashmdash

mdashBO

S1716

GeneID

mapping

(orie

ntationlowast

)

4780

178095031minus178129859(minus)

1010

9881

2165356974minus

165392728(minus)

7426

22181721941minus181756837(minus)

4788

1320989206minus21021893

(minus)

4970

2419659540minus19692048

Ensembleg

eneID

(mapping

)EN

SG00

00011604

4(178092323minus178257425)

mdashEN

SPTR

G00

000012677

(181721949minus181756285)

ENSC

AFG

0000

0013506

(20987569minus

21022230)

ENSB

TAG00

000019255

(19659540minus19692048)

RefSeq

IDm

RNA

size

NM

006164

4(G

I372620346)2859b

p

XM0039908931

(GI410968909)

predicted2394

bp

XM00114

58762


2850

bp

XM5359753

(GI345797173)

predicted2570

bp

NM

0010116

782

(GI147904941)240

9bp

ProteinID

(aaMW

sect )NP00

61552

(60567696)

XP0039909421

(60667797)

XP00114

58762

(60567686)

XP5359751

(60167087)

NP0010116

782

(60767813)

UniProt

IDQ16236

mdashA2T

6Y9

mdashQ5N

UA62

Varia

nts

14transcrip

ts12

isoform

s3transcrip

ts3iso

form

s5transcrip

ts5iso

form

s2transcrip

ts2iso

form

smdash

Hom

olog

ygeneprotein

100100

893914

999999

893888

905891


Table1Con

tinued

Species

Rhesus

mon

key

Macacamulatta

Chicken

Gallusgallus

Zebrafish

Daniorerio

Mou

seMus

musculus

Rat

Rattu

snorvegicus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2nu

clear


2lik

e2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdash

Genes

ynon

yms

NFE

2L2NRF

2Mmu966

NFE

2L2NRF

2nfe2l2N

rf2N

rf2a

wufc15g09wufj6

7e03

Nfe2

l2N

rf2A

I194320

Nfe2

l2N

rf2

Chromosom

emap

127

92C

3(4475

cM)

3q23

Genom

esequence

(NCB

IBuild)

NC

0078691

NC

0060

943

NC

0071205

(Zv9)

NC

0000

687

(GRC

m38p1)

NC

0051023

(Rno

r50)

Prim

arySource

mdashCG

NC

4960

4ZF

INZ

DB-GEN

E-030723-2

MGI108420

RGD620360

GeneIDmapping

(orie

ntationlowast

)70

7606

40848940minus40

8846

00(minus)

3960

1415304546minus15320356

3601

491643746minus

1670288

1802

475675519minus757046

41(minus)

8361

969041647minus69069070

(minus)

Ensembleg

eneID

(mapping

)EN

SMMUG00

0000

01861

(40848948minus

40884174)

ENSG

ALG

0000

0009240

(16897956minus

16922637)

ENSD

ARG

0000

0042824

(1643631minus1672715)

ENSM

USG

0000

0015839

(75675513minus

757046

41)

ENSR

NOG00

0000

01548

(58366

693minus

58394118)

RefSeq

IDm

RNA

size

NM

0012576071

(GI383872375)2335b

pNM

2051171

(GI45384113)2555

bpNM

1828891

(GI33504557)2149

bpNM

0109023

(GI76573877)2469

bpNM

0317892

(GI402692377)2305b

pProteinID

(aaMW

sect )NP001244

5361

(606

67703)

NP9904

481

(58265160)

NP8783091

(58665757)

NP0350321

(59766770)

NP1139771

(59766825)

UniProt

IDF7GPD

8Q90834

Q8JIM

1Q60795

O54968

Varia

nts

2transcrip

ts2iso

form


1transcript1isoform

1transcript

1transcript1isoform

Hom

olog

ygeneprotein

988990

726674

546491

834825

838832

Referto

httpwwwncbinlm

nihgovhom

ologene2412

and

reference


molog

yDetails

ofho

molog

yscores

and

sequ

encescan

bealso

obtained

byblastagainsthu

man

sequ

ence

(http

blastn

cbin

lmnihgov)

Furtherinform

ation

ontranscrip

tvaria

ntsand

protein

isoform

sareview

able

bygene

IDat

NCB

I(http

wwwncbinlm

nihgovrefseqrsg)

and

eEn

semble

(http

useastensembleo

rgin

dexhtml)or

byproteinID

atUniProt(http

wwwun

iproto

rg)

sect MWpredicted

molecularweightfrom

NCB

I(MW

inUniProtvarie

sslightly)Re

fSeqreference

sequ

enceaaam

ino

acidsandlowastgene

incomplem

ento

rientation




Neh216ndash89





(Keap1-independent)

Neh1435ndash568















minus400

minus500

minus50minus100

minus200

minus300

minus450

minus350

minus250

minus150

g minus

g


pV268M

pR517K pH453L



51101151201251301351401451501551601





151

101151201251301351401451501551601

2351


old + 1 [22]

g minus1 (178130354)

c minus96delC




p R43Q p R43W



c 9minus95

g minus178

c minus304

c 8minus13

c 2minus16

TgtA

CgtT

GgtA

GgtA

GgtA

GgtT

GgtCAgtG

AgtCAgtG



4versus GCC

5







inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table1Con

tinued

Species

Rhesus

mon

key

Macacamulatta

Chicken

Gallusgallus

Zebrafish

Daniorerio

Mou

seMus

musculus

Rat

Rattu

snorvegicus

Officialfullname

nucle

arfactor

(erythroid-derived

2)-like

2nu

clear


2lik

e2Antho

rnam

enu

clear

factor

erythroid2-related

factor

2NF-E2

-related

factor

2NFE

2-related

factor

2Antho

rnam

eHEB

P1mdash

mdashmdash

mdash

Genes

ynon

yms

NFE

2L2NRF

2Mmu966

NFE

2L2NRF

2nfe2l2N

rf2N

rf2a

wufc15g09wufj6

7e03

Nfe2

l2N

rf2A

I194320

Nfe2

l2N

rf2

Chromosom

emap

127

92C

3(4475

cM)

3q23

Genom

esequence

(NCB

IBuild)

NC

0078691

NC

0060

943

NC

0071205

(Zv9)

NC

0000

687

(GRC

m38p1)

NC

0051023

(Rno

r50)

Prim

arySource

mdashCG

NC

4960

4ZF

INZ

DB-GEN

E-030723-2

MGI108420

RGD620360

GeneIDmapping

(orie

ntationlowast

)70

7606

40848940minus40

8846

00(minus)

3960

1415304546minus15320356

3601

491643746minus

1670288

1802

475675519minus757046

41(minus)

8361

969041647minus69069070

(minus)

Ensembleg

eneID

(mapping

)EN

SMMUG00

0000

01861

(40848948minus

40884174)

ENSG

ALG

0000

0009240

(16897956minus

16922637)

ENSD

ARG

0000

0042824

(1643631minus1672715)

ENSM

USG

0000

0015839

(75675513minus

757046

41)

ENSR

NOG00

0000

01548

(58366

693minus

58394118)

RefSeq

IDm

RNA

size

NM

0012576071

(GI383872375)2335b

pNM

2051171

(GI45384113)2555

bpNM

1828891

(GI33504557)2149

bpNM

0109023

(GI76573877)2469

bpNM

0317892

(GI402692377)2305b

pProteinID

(aaMW

sect )NP001244

5361

(606

67703)

NP9904

481

(58265160)

NP8783091

(58665757)

NP0350321

(59766770)

NP1139771

(59766825)

UniProt

IDF7GPD

8Q90834

Q8JIM

1Q60795

O54968

Varia

nts

2transcrip

ts2iso

form


1transcript1isoform

1transcript

1transcript1isoform

Hom

olog

ygeneprotein

988990

726674

546491

834825

838832

Referto

httpwwwncbinlm

nihgovhom

ologene2412

and

reference


molog

yDetails

ofho

molog

yscores

and

sequ

encescan

bealso

obtained

byblastagainsthu

man

sequ

ence

(http

blastn

cbin

lmnihgov)

Furtherinform

ation

ontranscrip

tvaria

ntsand

protein

isoform

sareview

able

bygene

IDat

NCB

I(http

wwwncbinlm

nihgovrefseqrsg)

and

eEn

semble

(http

useastensembleo

rgin

dexhtml)or

byproteinID

atUniProt(http

wwwun

iproto

rg)

sect MWpredicted

molecularweightfrom

NCB

I(MW

inUniProtvarie

sslightly)Re

fSeqreference

sequ

enceaaam

ino

acidsandlowastgene

incomplem

ento

rientation




Neh216ndash89





(Keap1-independent)

Neh1435ndash568















minus400

minus500

minus50minus100

minus200

minus300

minus450

minus350

minus250

minus150

g minus

g


pV268M

pR517K pH453L



51101151201251301351401451501551601





151

101151201251301351401451501551601

2351


old + 1 [22]

g minus1 (178130354)

c minus96delC




p R43Q p R43W



c 9minus95

g minus178

c minus304

c 8minus13

c 2minus16

TgtA

CgtT

GgtA

GgtA

GgtA

GgtT

GgtCAgtG

AgtCAgtG



4versus GCC

5







inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of




Neh216ndash89





(Keap1-independent)

Neh1435ndash568















minus400

minus500

minus50minus100

minus200

minus300

minus450

minus350

minus250

minus150

g minus

g


pV268M

pR517K pH453L



51101151201251301351401451501551601





151

101151201251301351401451501551601

2351


old + 1 [22]

g minus1 (178130354)

c minus96delC




p R43Q p R43W



c 9minus95

g minus178

c minus304

c 8minus13

c 2minus16

TgtA

CgtT

GgtA

GgtA

GgtA

GgtT

GgtCAgtG

AgtCAgtG



4versus GCC

5







inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of





minus400

minus500

minus50minus100

minus200

minus300

minus450

minus350

minus250

minus150

g minus

g


pV268M

pR517K pH453L



51101151201251301351401451501551601





151

101151201251301351401451501551601

2351


old + 1 [22]

g minus1 (178130354)

c minus96delC




p R43Q p R43W



c 9minus95

g minus178

c minus304

c 8minus13

c 2minus16

TgtA

CgtT

GgtA

GgtA

GgtA

GgtT

GgtCAgtG

AgtCAgtG



4versus GCC

5







inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of



inprom

oter

andexon

sofh

uman

NRF

2

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs16865105

g178136629AgtC

cminus555minus

6770Tgt

G51015840Flanking

(minus6770)

SNP

C=01928421

1000

Genom

esrs7557529

g178135097CgtT

cminus555minus

5238GgtA

51015840Flanking

(minus5238)

SNP

nars6750320

g178131796CgtT

cminus555minus

1937GgtA

51015840Flanking

(minus1937)

SNP

T=0030266

1000

Genom

esrs18116

2518

g178131774TgtC

cminus555minus

1915AgtG

51015840Flanking

(minus1915)

SNP

C=000

051

1000

Genom

esrs1900

44775

g178131746CgtT

cminus555minus

1887GgtA

51015840Flanking

(minus1887)

SNP

T=000

051

1000

Genom

esrs185117338

g178131704AgtG

cminus555minus

1845Tgt

C51015840Flanking

(minus1845)

SNP

G=000

051

1000

Genom

esrs149947189

g178131697CgtT

cminus555minus

1838GgtA

51015840Flanking

(minus1838)

SNP

T=000

092

1000

Genom

esrs139771244

g178131625AgtG

cminus555minus

1766Tgt

C51015840Flanking

(minus1766)

SNP

G=000

092

1000

Genom

esrs6747203

g17813160

4CgtG

cminus555minus

1745GgtC

51015840Flanking

(minus1745)

SNP

G=000

613

1000

Genom

esrs193101749

g178131504TgtC

cminus555minus

1645AgtG

51015840Flanking

(minus1645)

SNP

C=000

4610

1000

Genom

esrs190630762

g178131495GgtC

cminus555minus

1636Cgt

G51015840Flanking

(minus1636)

SNP

C=000

092

1000

Genom

esrs183764

402

g178131366CgtA

cminus555minus

1507GgtT

51015840Flanking

(minus1507)

SNP

A=000

051

1000

Genom

esrs19122296

4g178131211GgtA

cminus555minus

1352Cgt

T51015840Flanking

(minus1352)

SNP

A=000

092

1000

Genom

esrs187137522

g178131165TgtG

cminus555minus

1306AgtC

51015840Flanking

(minus1306)

SNP

G=000

092

1000

Genom

esrs182620359

g178131158AgtG

cminus555minus

1299Tgt

C51015840Flanking

(minus1299)

SNP

G=000

051

1000

Genom

esrs4893819

(rs61433302)

g178131134CgtT

cminus555minus

1275GgtA

51015840Flanking

(minus1275)

SNP

C=04263931

1000

Genom

es

rs191547130

g178131017CgtT

cminus555minus

1158GgtA

51015840Flanking

(minus1158)

SNP

T=000

051

1000

Genom

esrs188422217

g178131003AgtG

cminus555minus

1144TgtC

51015840Flanking

(minus114

4)SN

PG=000143

1000

Genom

esrs143047764

g178130865AgtG

cminus555minus

1006Tgt

C51015840Flanking

(minus1006)

SNP

G=000

6915

1000

Genom

esrs74432849

g178130766CgtA

cminus555minus

907GgtT

51015840Flanking

(minus907)

SNP

nars116

79252

g178130691CgtG

cminus555minus

832GgtC

51015840Flanking

(minus832)

SNP

nars12993217

g178130516AgtG

cminus555minus

657TgtC

51015840Flanking

(minus657)

SNP

nars115644

826

g17813044

2TgtA

cminus555minus

583AgtT

51015840Flanking

(minus583)

SNP

A=0015133

1000

Genom

esrs140803524

g178130431GgtA

cminus555minus

572CgtT

51015840Flanking

(minus572)

SNP

A=000

4610

1000

Genom

es

rs776844

20g178130427TgtC

cminus555minus

568AgtG

51015840Flanking

(minus568)

SNP

C=0033974

C=0190(84)

1000

Genom

es[24]

rs183651094

g178130336AgtT

cminus555minus

477TgtA

51015840Flanking

(minus477)

SNP

T=000184

1000

Genom

es

rs35652124

sect

(rs57695243)

g178130073TgtC

cminus555minus

214AgtG

51015840Flanking

(minus214)

SNP

C=03512767

T=0429(84)

T=0413181Dagger

C=033827Dagger

C=03517

69

1000

Genom

es[24]

[22]

[23]

[25]

rs6706649

sectg178130071CgtT

cminus555minus

212GgtA

51015840Flanking

(minus212)

SNP

T=0078170

T=004

8(84)

T=004

821Dagger

T=00753Dagger

1000

Genom

es[24]

[22]

[23]

rs1506

48896

g178130047CgtG

cminus555minus

188GgtC

51015840Flanking

(minus188)

SNP

G=000235

G=000

6(84)

1000

Genom

es[24]

rs6721961

sect

(rs117801448)

g178130037TgtC

TgtG

cminus555minus

178AgtC

AgtG

51015840Flanking

(minus178)

SNP

T=0150328

T=0283124Dagger

T=031325Dagger

T=0321(84)

1000

Genom

es[22]

[23]

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs20134560

4g178129924178129925insG


51015840Flanking

(minus66minus65)

Insertion

G=0017939

1000

Genom

es

rs200432479

g178129741178

129742delAA


Texon

1UTR

-51015840(118minus119

)Dele

tion

-=000378

-=000

6(84)

1000

Genom

es[24]

rs75485459

g178129608CgtA

cminus304GgtT

Exon

1UTR

-51015840(252)

SNP

nars192086766

g17812946

6CgtT

cminus162GgtA

Exon

1UTR

-51015840(394)

SNP

T=002248

1000

Genom

esmdash

g17812944

2GgtA

cminus138CgtT

Exon

1UTR

-51015840(418)

SNP

A=0012(84)

[24]

rs7166

8246

g17812940

0delG

cminus96delC

Exon

1UTR

-51015840(460)

Dele

tion

nars187291840

g178129399CgtT

cminus95GgtA

Exon

1UTR

-51015840(461)

SNP

T=0054912

01000

Genom

es

rs143406266

g178129391178129393delGGC


Exon

1UTR

-51015840(467minus469)

Dele

tion

-=064

4282Dagger

-=0589(84)

[22]

[24]

rs182428269

g178098918GgtA

c127Cgt

TEx

on2(682)

Cns(pArg43Trp)

A=000

051

1000

Genom

esrs35248500

g178098917CgtT

c128GgtA

Exon

2(683)

Cns(pArg43Gln)

T=000

613

1000

Genom

esrs1135118

g178098831CgtT

c214GgtA

Exon

2(769)

Cns(pAla72Th

r)TDagger

[23]

rs19969166

0g178098829AgtT

c216Tgt

AEx

on2(771)

Cs(pAla72=)

namdash

g178098769GgtA

c276Cgt

TEx

on2(831)

Cs(pIle92=)

TDagger[23]

rs5031039

g178098750AgtG

c295Tgt

CEx

on2(850)

Cns(pSer99P

ro)

G=0Dagger

[23]

rs200239262

g178098017CgtG

c363GgtC

Exon

3(918)

Cns(pGln121H

is)na

rs183034165

g178098008TgtC

c372GgtA

Exon

3(927)

Cs(pAla124=

)T=000

092

T=000

6(84)

1000

Genom

es[24]

rs199970826

g178097996CgtT

c384GgtA

Exon

3(939)

Cs(pPro128=

)T=000

051

1000

Genom

esrs201992337

g178097260CgtT

c454GgtA

Exon

4(100

9)Cn

s(pGlu152Lys)

nars201589693

g178097251CgtT

c463GgtA

Exon

4(1018)

Cns(pV

al155Ile)

T=000

051

1000

Genom

es

rs35577826

g178097185AgtC

c529Tgt

GEx

on4(1084)

Cns(pLeu177Va

l)C=000143

Alt0005Dagger

1000

Genom

es[23]

rs181513314

g178096710CgtT

c621GgtA

Exon

5(1176)

Cn(pLeu207=

)T=000

051

1000

Genom

esrs60132461

g178096675TgtC

c656AgtG

Exon

5(1211)

Cns(pLys219Arg)

C=000184

1000

Genom

es

rs139187151

g178096634GgtA

c697Cgt

TEx

on5(1252)

Cns(pPro233Ser)

A=000

051

A=0012Dagger

(84)

1000

Genom

es[24]

rs35557421

g178096620d

elT

c711delA

Exon

5(1266)

Fram

eshiftdeletio

n(pLys237=fs)

na

rs34154613

g178096529CgtT

c802GgtA

Exon

5(1357)

Cns(pV

al268M

et)

T=000184

1000

Genom

esrs141363120

g178096

406GgtA

c925Cgt

TEx

on5(14

80)

Cns(pLeu309Ph

e)A=000378

1000

Genom

esrs201661476

g178096380AgtC

c951Tgt

GEx

on5(1506)

Cns(pIle

317M

et)

na


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs199673454

g178096309TgtA

c1022AgtT

Exon

5(1577)

Cns(pAs

p341Va

l)A=000

051

1000

Genom

esrs35007548

g178096299GgtA

c1032CgtT

Exon

5(1587)

Cs(pSer344=

)A=000

092

1000

Genom

esrs200209692

g178096287TgtC

c104

4AgtG

Exon

5(1599)

Cs(pLeu348=

)C=000

051

1000

Genom

es

mdashg178096237CgtA

c1094GgtT

Exon

5(1649)

Cns(pSer365Ile

)A=0125273

A=000

6Dagger(84)

PubM

ed[24]

rs201214197

g178096171CgtT

c1160GgtA

Exon

5(1715)

Cns(pSer387Asn)

T=000

051

1000

Genom

esrs200494292

g178096165TgtC

c1166AgtG

Exon

5(1721)

Cns(pLys389Arg)

nars186171287

g178096115GgtA

c1216CgtT

Exon

5(1771)

Cns(pPro4

06Ser)

A=000

051

1000

Genom

esrs182276775

g178096062CgtA

c1269GgtT

Exon

5(1824)

Cns(pGlu423A

sp)

A=000

051

1000

Genom

esrs201560221

g17809604

8TgtC

c1283AgtG

Exon

5(1838)

Cns(pLys428Arg)

nars189238236

g178096043AgtG

c1288TgtC

Exon

5(1843)

Cs(pLeu430=

)G=000

051

1000

Genom

esrs184287392

g178096022GgtA

c1309CgtT

Exon

5(1864)

Cns(pArg437Trp)

A=000

051

1000

Genom

esrs201871588

g178095986GgtA

c1345CgtT

Exon

5(19

00)

Cns(pAg449Cy

s)na

rs181294188

g178095985TgtC

c1346GgtA

Exon

5(19

01)

Cns(pArg44

9His)

T=000

092

1000

Genom

esrs20169046

6g178095973TgtA

c1358AgtT

Exon

5(19

13)

Cns(pHis4

53Leu)

A=000

051

1000

Genom

esrs105704

4(rs52789869)

g178095781CgtT

c1550GgtA

Exon

5(2105)

Cns(pArg517Lys)

TDagger[23]

rs200750800

g178095603AgtG

c1728TgtC

Exon

5(2283)

Cs(pTyr576=

)na

rs200175942

g178095567AgtG

c1764TgtC

Exon

5(2319)

Cs(pAsp588=

)G=000

051

1000

Genom

esrs77547666

g178095495GgtC

clowast18Cgt

GEx

on5UTR

-31015840(2391)

SNP

C=000

6915

1000

Genom

esrs73031353

g178095425TgtC

clowast88AgtG

Exon

5UTR

-31015840(2461)

SNP

C=000184

1000

Genom

esrs675944

3g178095345TgtC

clowast168AgtG

Exon

5UTR

-31015840(2541)

SNP

C=000

419

1000

Genom

esrs188674558

g178095279CgtA

clowast234GgtT

Exon

5UTR

-31015840(2607)

SNP

A=000

051

1000

Genom

esrs77685897

g178095247AgtG

clowast266TgtC

Exon

5UTR

-31015840(2639)

SNP

G=000

092

1000

Genom

esrs1057092

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars3197704

g178095162TgtG

clowast351AgtC

Exon

5UTR

-31015840(2724)

SNP

nars184701151

g178095159TgtC

clowast354AgtG

Exon

5UTR

-31015840(2727)

SNP

C=000276

1000

Genom

esrs11543307

g178095153AgtG

clowast360TgtC

Exon

5UTR

-31015840(2733)

SNP

nars111874043

g178095146AgtG

clowast367TgtC

Exon

5UTR

-31015840(2740)

SNP

nars34012004

g178095102AgtC

clowast411TgtG

Exon

5UTR

-31015840(2784)

SNP

C=0071

[24]


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table3Con

tinued

IDMap

onchromosom

e2lowast

(HGVS

name)

Positionin

Nfe2

l2

(HGVS

name)

Region

s(position

from

mRN

A)

Varia

tioncla

ssand

consequences

(HGVS

name)dagger

Minor

allelefrequ

ency

(MAF)

MAcoun

tsDagger(coh

ort

size)

MAFsources

rs201481890

g178095090178095091in

sTclowast

422lowast423insA

Exon

5UTR

-31015840

(2795minus

2796)

Insertion

na

rs3082500

g178095089178095090d

elTT

delTTinsT


elAAinsA

Exon

5UTR

-31015840

(2796minus

2797)

Dele

tion

insertion

na

rs71792546

(rs71796710)

g178095079d

elT

clowast425delA

Exon

5UTR

-31015840(2798)

Dele

tion

na

rs1057106

g178095078AgtC

AgtT

clowast435TgtA

TgtG

Exon

5UTR

-31015840(2808)

SNP

na

rs34176791

g178095076AgtC

clowast437TgtG

Exon

5UTR

-31015840(2810)

SNP

C=000235

1000

Genom

esrs35911553

g178095045CgtT

clowast46

8GgtA

Exon

5UTR

-31015840(2841)

SNP

T=000

6915

1000

Genom

esSequ

ence

varia

tions

inup

stream

andexon

sofh

uman

NRF

2fro

m655varia

tions

availablein

publicdatabase

asof

Decem

ber2012

(583

activ

esomeSN

Psmergedge14

SNPs

citedin

PubM

ed)lowastNCB

Ireference

sequ

ence

NC

0000

0211

(Hom

osapiens

chromosom

e2G

RCh37p

10prim

arya

ssem

bly)spanning

178095033ndash1781298

59bp

(com

plem

ent34827

bpforexons

andintro

ns)51015840-Flank

ingregions

startat17812

9860

bp(minus1)in

transcrip

tvariant

1HGVS

Hum

anGenom

eVa

riatio

nSo

ciety

Position

sinvaria

nt1(NM

006164

4)2859

bpsectSN

Pscitedin

PubM

edE

xon11781298

59ndash17812

9260

(600

bpT

TS=1781293

04)exon

2178098999ndash

178098733(267

bp)exon

3178098067ndash1780979

78(90b

p)exon41780973

11ndash178097120

(192b

p)and

exon

5178096736ndash

178095033(1704b

p)daggerProteinam

inoacid

(aa)

resid

uesiniso

form

1(N

P00

61552605

aa)Cn

scoding

-non

syno

nymou

sCs

cod

ing-syno

nymou


tavailable


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table4Hum

anNRF

2SN

Psassociated

with

diseaser

isk

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

rs7557529

g178135097CgtT

minus5238

Ggt

AParkinsonrsquos

disease(2010

[26])

G=0718252Dagger

inhaplotype

OR=090

or040

CI=

060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2886162

g178133165AgtG

minus3306

TgtC

Breastcancer

survival(2012[27])

TT=0324

OR=16

87C

I=1105ndash275

FinlandKB

CP(452)

Chronicg

astritisgastric

ulcer(2007

[28])

GDagger

GDaggerin

haplotypefor

ulcer(OR=

252C

I=119ndash

545)

Japanese

(159)

P14methylationin

gastric

cancer

Hpyloriinfectio

n(2008[29])

Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-n

egative

cases(2008

[30])

Ain

haplotype

119875=0022

Japanese

(209)

rs35652124

(rs57695243)

g178130073TgtC

minus214Agt

G(previou

slyminus653[23]

orminus686[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Lupu

swith

neph

ritisin

female(2010

[25])

GA

OR=18

1CI

=10

4ndash312

Mexican

mestizo(362)

Parkinsonrsquos

disease(2010

[26])

A=0884312Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

COPD

(2010[32])

G=052Dagger

hazard

ratio

=095C

I=091ndash0

99

(Haplotype)

German

(69)

Gastriculcer(2007

[28])

GDaggerin

haplotype

OR=252C

I=119ndash

545

Japanese

(159)

P14methylationin

gastric

cancer

H


Gin

haplotype

OR=290C

I=114ndash

736

Japanese

(209)

Gastriccancer

inHpylori-negative

cases(2008

[30])

Gin


Japanese

(209)

rs6706

649

g178130071CgtT

minus212Ggt

A(previou

slyminus651[23]

orminus684[22])

Ulcerativec

olitis(2008

[31])

AG

(OR=045C

I=022ndash0

93)

G(O

R=257C

I=10

1ndash660)

Japanese

(89)

Maternalacetaminop

henandasthma

(2010[33])

A=02321137Dagger

OR=17

3CI

=12

2245

UKALSPA

C(gt40

00mothersgt

5000

child

ren)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

COPD

(2010[32])

G=098Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

Parkinsonrsquos

disease(2010

[26])

G=0972343Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

03ndash06

Swedish

Polish

Caucasian

(357)

Acutelun

ginjury

follo

wingtrauma

(2007[23])

CA=0119Dagger

OR=644

CI=

134ndash

3080

Caucasia

nAfrican-

American

(164

)

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Vitiligo(2008[35])

CAA

AOR=17

24C

I=13

5ndash221

Chinese(300)

COPD

(2010[32])

G=073Daggerin

haplotype

hazard

ratio

=095C

I=091ndash0

99

German

(69)

rs6721961

(rs117801448)

g178130037TgtC

TgtG

minus178Agt

GAgt

C(previou

slyminus617[23]

orminus650[22])

Parkinsonrsquos

disease(2010

[26])

C=0980346Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Postm

enop

ausalvenou

sthrombo

embo

lism

(2011[36])

A=033311

OR=25CI

=370ndash8570

Caucasia

n(161)

Breastcancer

survivalandNRF

2proteinexpressio

n(2012[27])

AA

OR=4656CI

=13

5ndash1606

FinlandKB

CP(452)

Acutelun

ginjury-related

mortality

followingsyste

micinflammatory

respon

sesynd

rome(2012

[37])

GG

OR=97

3CI

=12

7ndash7480

Caucasia

n(750)

Infection-indu

cedasthma(

2012

[38])

AC

OR=0437CI

=028ndash0

80

Hun

garia

nCaucasia

nGypsy

(307)

rs143406266

g178129391178

129393delGGC

Exon

1(467ndash4

69G

CC)

COPD

(2010[32])

GCC

4=053Dagger

hazard

ratio

=095C

I=091ndash0

99

Taiwanese(69)

rs2886161

g178127839Tgt

ClowastIntro

n1

Parkinsonrsquos

disease(2010

[26])

T=0878309Dagger

inhaplotype

OR=09or

04CI

=06ndash

14or

03ndash06

Swedish

Polish

Caucasian

(357)

rs2364723

g178126546Ggt

CIntro

n1

Basaland

smoker

FEV

1(200

9[39])


=0525Dagger

Also

ashaplotype

Netherla

nd(2542)

rs2364722

g178124787Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

rs13001694

g178118990Agt

GIntro

n1

Basaland

smoker

FEV

1(200

9[39])

G=040

11578Dagger

inhaplotype

Netherla

nd(2542)


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table4Con

tinued

IDMap

onchromosom

e2 (H

GVS

name)

Region

class

Dise

asea

ssociatio

nandreferences

Risk

allelesa

ndstatistics

Ethn

icgrou

p(num

bero

fcase)

Breastcancer

[40]

Twith

NQO1N

OS3H

O1risk

allelesOR=15

6CI

=097ndash251

Caucasia

nandothers(505)

rs1806

649

(rs58745895)

g178118152Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=02631119Daggerin

haplotype

CI=minus8730ndash

(minus17

0)Netherla

nd(2542)

Parkinsonrsquos

disease(2010

[26])

T=0422148Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

Particulatem

attera

ndasthmaCO

PDadmiss

ion(2012[41])

Cwith

lowvitamin

Clevel(OR=

31CI

=15

0ndash630)

UK(209)

rs4243387

(rs6003846

4)g178117765Cgt

TIntro

n1

Basaland

smoker

FEV

1(200

9[39])

T=00914

25Daggerin

haplotype

Netherla

nd(2542)

rs1962142

(rs58448508)

g178113484Agt

GIntro

n1

Ann

ualF

EV1decline

(2011[34])

A=0082in

haplotype

Japanese

(915)

Breastcancer

NRF

2andARE

expressio

n(2012[27])

A(119875=0036)

FinlandKB

CP(452)

rs6726395

(rs57309289)

g178103229Agt

GIntro

n1

Smok

ing-relatedFE

V1decline

and

annu

alFE

V1decline

(2011[34])

G=0884Dagger

A=0082in

haplotype

Japanese

(915)

Basaland

smoker

FEV

1(200

9[39])

G=046

41764Daggerin

haplotype

Netherla

nd(2542)

rs2001350

(rs17515179

rs60883775)

g178100

425Cgt

TIntro

n1

Ann

ualF

EV1decline

(2011[34])

T=0082in

haplotype

Japanese

(915)

Parkinsonrsquos

disease(2010

[26])

T=0986350Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs10183914

(rs58731187

rs61374844

)g17809766

6Cgt

TIntro

n3

Parkinsonrsquos

disease(2010

[26])

T=0536188Dagger

inhaplotype

OR=09or

04CI

=060ndash140or

030ndash0

60

Swedish

Polish

Caucasian

(357)

rs2706110

g178092162Tgt

C31015840Flanking

Breastcancer

(2012[27])

TT

OR=2079CI

=118ndash368

FinlandKB

CP(452)

rs2588882

g178087165Ggt

T31015840Flanking

Infection-indu

cedasthma(

2012

[38])

TG

OR=0290CI

=013ndash0

62

Hun

garia

nCaucasia

nGypsy

(307)

minus686in

reference[22]

=minus653in

reference[23]


reference[22]



=minus617in

reference[23]


romosom

econtig(in

tron

31015840flank

ing)

orreversed

(51015840flank

ingprom

oter)a

llelesinbo

ldhave

been

used

inthetextand

TableOR

odds

ratio

CI95confi

denceinterval











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of











10)


10concentration




















pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of













pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


pL575M

pF71L

pH543QpL451V






51101151201251301351401451501551

minus400

minus500

minus50

minus100

minus200

minus300

minus450

minus350

minus250

minus150

minus950

minus900

minus850

minus800

minus750

minus700

151

101151201

2001


c minus41c minus

c

c

c c

gg minus 6C


g minus281delC




g minus41

246

440

minus381

minus11

minus91 minus90

minus332

minus153

minus98



g 460CgtT


CgtTCgtG

g minus320CgtT

CgtT

CgtT

CgtTg minus426GgtA

GgtACgtA

CgtA

GgtA

g minus238GgtTTgtC

TgtC

TgtC

TgtCTgtG

g minus229AgtG

CgtG

CgtG

GgtC



151

201251301351401451501551601


Neh2

Neh3

Neh4Neh5

Neh6

Neh1


101151



Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table5Mou

seup

stream

andexon

varia

tions

ofNfe2

l2locusin17

inbred

strainsR

eference

sequ

ence

isC5

7BL6J

(B6strain

1)geno


geno

typesareshow

nas

chromosom

econ

tigsequ

enceStrains

2129S1S

vlmJ3AJ

4AKR

J5BA

LBcJ6C3

HH

eJ7C

57BL

6NJ8CA

STEiJ9CB

AJ

10D

BA2J11FVBNJ12LPJ

13N

ODShiLtJ14N

ZOH

ILtJ

15P

WK

PhJ16SPR

ETEiJ

17W

SBEiJ

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs2566

08517

75705565

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

AA

Grs47274959

75705562

AT

(TA


NC

AT

TA

TT

AA

TT

AT

AT

TT

Ars216940398

75705554ndash75705555

Tadd(A

add)


NC

CGrs239114134

75705540

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

CT

Crs46

461765

75705528

TG(A

C)oA

C


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs5144

9853

75705525

CA(G

T)


NC

CA

AC

AA

CC

AA

CA

CA

CC

Crs249093111

75705512

CT(G

A)


NC

CT

TC

TT

CC

TT

CT

CT

TT

Crs263745200

75705510

CG(G

C)


NC

GG

GG

GG

GG

GG

GG

GG

CG

Grs45651867

75705498

TG(A

C)


NC

TG

GT

GG

TT

GG

TG

TG

GG

Trs219997531

75705495

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs251918379

75705451

TA(A

T)


NC

TT

TT

TT

TT

TT

TT

TT

TA

Trs27978306

75705449

TA(A

T)


NC

TA

AT

AA

TT

AA

TA

TA

TT

Trs216087412

75705429

TG(A

C)lowast


NC

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

TlowastTlowast

GTlowast

Tlowast

rs261229914

75705423ndash75705424

AGdel(CT

del)


NC

AGrs27978307

75705400

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs243167395

75705359

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs27978308

75705307

GA

(CT)


6NC

GG

GG

GG

GG

GG

GG

GG

AG

Grs254744

09875705294

AT

(TA


NC

AA

AA

AA

AA

AA

AA

AA

AT

Ars228133419

75705179

GT

(CA


NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs214719520

75705111

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs2440

87730

75705101

GA

(CT)


0NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs227781699

75705081

CG(G

C)


0NC

CC

CC

CC

CC

CC

CC

CC

GC

Crs257870353

75705067

CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs24487744

075705022

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars234628138

75704973

AC

(TG


NC

AA

AA

AA

AA

AA

AA

AA

AC

A


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs247275247

75704961

GA

(CT)


NC

GG

GG

GG

GG

GG

GG

AG

GG

Grs247519047

75704922

Gdel(Cdel)


NC

Grs27978309

(rs51915758)

75704887

GA

C(C

TG


NC

GA

AG

AA

GG

AA

GA

GA

CC

G

rs218139102

75704879

CA(G

T)


NC

CC

CC

CC

CC

CC

CC

CC

AC

Crs251990355

75704870

TC(A

G)


NC

TT

TT

TT

TT

TT

TT

TT

TC

Trs238746955

75704794

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

GA

Ars221664

405

75704786

AG

(TC)


NC

AA

AA

AA

AA

AA

AA

AA

AG

Ars217054035

75704766

ndash75704767

GAAadd(TTC

add)


NC

GA

rs248182931

75704759ndash75704760

Gadd(C

add)


minus119

NC

AGrs217197904

75704744

GA

(CT)


(+)S

p1[23]

GA

AG

AA

GG

AA

GA

AA

GG

Ars2644

9364975704704

Gdel(Cdel)


NC

Grs2404

81112

757046

82CT(G

A)


NC

CC

CC

CC

CC

CC

CC

CC

CT

Crs27978310

75704617

AG

(TC)

UTR

-525

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars27978311

75704610

CG(G

C)

UTR

-532

NC

GG

GG

GG

GG

GG

GG

GG

GG

Crs27978312

757046

05GA

(CT)

UTR

-537

NC

GA

AG

AA

GG

AA

GA

GA

GG

Grs214784220

757044

99AG

(TC)

UTR

-5143

NC

AA

AA

AA

AA

AA

AA

AA

GG

Ars244146318

757044

98GT

(CA

)UTR

-5144

NC

GG

GG

GG

GG

GG

GG

GG

GT

Grs27978313

757044

97GC

(CG

)UTR

-5145

NC

GC

CG

CC

GC

CC

GC

CC

CC

Crs215431944

757044

93CT(G

A)

UTR

-5149

NC

CC

CC

CC

CC

CC

CC

CC

TC

Crs257015697

757044

49GA

(CT)

UTR

-5193

NC

GG

GG

GG

GG

GG

GG

GG

GA

Grs252234782

757044

19GT

(CA

)UTR

-5223

NC

Grs1346

0861

75679262

AG

(TC)

Exon

244

6Cn

sF71L

AG

GA

GG

AG

GG

AG

AG

GG

Grs1346

0859

75679202

GA

(CT)lowast

Exon

2506

CsH91=

GA

AG

AA

GG

AA

GA

GA

GG

Grs27978436

75679187

GA

(CT)lowast

Exon

2521

CsT9

6=G

GG

GG

GG

AG

GG

GG

GA

GG

rs226131070

75679178

GA

(CT)

Exon

2530

CsS99=

GG

GG

GG

GG

GG

GG

GG

GA

Grs227683834

75678576

AT

(TA

)Ex

on3

547

CnsV

105D

AA

AA

AA

AA

AA

AA

AA

AT

Ars257321187

75678506

TC(A

G)

Exon

3617

CsP128=

TT

TT

TT

TC

TT

TT

TT

TT

Trs27978444

75678500

TA(A

T)

Exon

3623

CsV130=

TT

TT

TT

TA

TT

TT

TT

AT

Trs227743136

75677686

GA

(CT)

Exon

4662

CsH143=

GG

GG

GG

GG

GG

GG

GG

GA

Grs215327202

75677664

CG(G

C)

Exon

4684

CnsA

151P

CC

CC

CC

CG

CC

CC

CC

CC

Crs247539755

75677663

GA

(CT)

Exon

4685

CnsA

151V

GG

GG

GG

GA

GG

GG

GG

GG

Grs233164

668

75677640

TC(A

G)

Exon

4708

CnsN

159D

TT

TT

TT

TT

TT

TT

TT

TC

T

rs2340

95816

75677162ndash75677160

GCT

del

(AGCdel)

Exon

5826minus

828

Cds-in

delQ

198

GCT


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Table5Con

tinued

SNPID

Chr2

locatio

n(bp)

SNPallele

Region

Locatio

nfro

mTS

Sreversed

SNP

allele

Con

sequ

ences

Strains

1 B62

34

56

78

910

1112

1314

1516

17

rs27978452

75677145

CT(G

A)

Exon

5843

CnsA

204T

CC

CC

CC

CC

CC

CC

CC

CC

T

rs225047937

75677086ndash75677078

GAG

ATCG

ATdel

(ATG

CATC

TCdel)

Exon

5902minus

910

Cds-in

del

(S224I225S226)

GAG

ATC

GAT

rs241469868

75676998

TA(G

T)

Exon

5990

CnT2

53S

TT

TT

TT

TT

TT

TT

TT

TA

Trs221602571

75676923

AC

(TG

)Ex

on5

1065

CnsS

278A

AA

AA

AA

AA

AA

AA

AA

AC

Ars252576472

75676876

GA

(CT)

Exon

51112

CsS293=

GG

GG

GG

GG

GG

GG

GG

GA

Grs250802933

75676841

TC(A

G)

Exon

5114

7Cn

sD305G

TT

TT

TT

TT

TT

TT

TT

TC

Trs225425698

75676792

CT(G

A)

Exon

5119

6Cs

P321=

CC

CC

CC

CC

CC

CC

CC

CT

Crs13459064

75676732

CT(G

A)

Exon

51256

CsT3

41=

CT

TC

TT

CT

TT

CT

CT

TC

Crs27978453

75676717

CT(G

A)

Exon

51271

CsA346=

CC

CC

CC

CC

CC

CC

CC

TC

Crs214335034

75676636

AG

(TC)

Exon

51352

CsD373=

AA

AA

AA

AA

AA

AA

AA

AG

Ars24958364

4756766

03AC

(TG

)Ex

on5

1385

CsP3

84=

AA

AA

AA

AA

AA

AA

AA

AC

Ars27978454

75676592

GA

(CT)

Exon

51396

CnsP

388L

GG

GG

GG

GG

GG

GG

GG

AG

Grs215384328

75676589

GC

(CG

)Ex

on5

1399

CnsA

389G

GG

GG

GG

GG

GG

GG

GG

GC

Grs251728286

75676571

GA

(CT)

Exon

51417

CnsT

395I

Grs247602334

75676567

TC(A

G)

Exon

51421

CsV396=

TT

TT

TT

TT

TT

TT

TT

TC

Trs234216231

75676530

TC(A

G)

Exon

51458

CnsM

409V

TT

TT

TT

TT

TT

TT

TT

TC

Trs212904337

75676526

CT(G

A)

Exon

51462

CnsR

410H

CC

CC

CC

CC

CC

CC

CC

CT

Crs252650779

75676522

TC(A

G)

Exon

51466

CsE4

11=

TT

TT

TT

TT

TT

TT

TT

TC

Trs231273560

75676516

TC(A

G)

Exon

51472

CsQ413=

TT

TT

TT

TT

TT

TT

TT

TC

Trs257886949

756764

13GT

(CA

)Ex

on5

1575

CsR4

48=

GG

GG

GG

GG

GG

GG

GG

GT

Grs241537608

756764

04GC

(CG

)Ex

on5

1584

CnsL

451V

GG

GG

GG

GG

GG

GG

GG

GC

Grs227619071

75676312

TC(A

G)

Exon

51676

CsQ481=

TT

TT

TT

TT

TT

TT

TT

TC

Trs258913831

75676290

AG

(TC)

Exon

51698

CsL4

89=

AA

AA

AA

AA

AA

AA

AA

AG

Ars225593319

75676126

AT

(TA

)Ex

on5

1862

CnsH

543Q

Ars4223233

75676105

GA

(CT)

Exon

51883

CsS550=

GG

GG

GG

GA

GG

GG

GG

GG

Grs4223232

75676032

GT

(CA

)Ex

on5

1956

CnsL

575M

Grs4223231

75675816

CG

UTR

-32172

NC

GG

GG

GG

GG

GG

GG

GG

GC

Grs1346

860

75675682

AT

UTR

-32306

NC

ASequ

ence

varia

tions

inmou

seNr

f2wereob

tained

from

Mou

sePh

enom

eDatabase(http

ph

enom

ejaxorgSNP)

andNCB

ISNPdatabase

(http

wwwncbinlm

nihgovSNP)N

CBIreference

sequ

ence

isMus

Musculusstra

inC5

7BL6J

chromosom

e2GRC

m38p1(NC

0000

687

GI37209910875704641ndash756755192

9123

bp)To

tal968

genetic

mutations

arerepo

rted

inNr

f2gene

and5k

bup

stream

(ge75704

642minus

1)and2k

bdo

wnstre


asof

Janu

ary2003A

llSN

Psandallelesa

representedas

geno

miccontig

(reversedsequ

ence

indicated)E

xon175704

641ndash75704364(278

bpT

TS=75704

408)

exon

275679431ndash756791

65(267

bp)exon

375678579ndash75678490(90b

p)exon475677713ndash756775

46(168

bp)andexon

57567718

4ndash75678849

(1666

bp)Proteinam

inoacid

(aa)

resid

uesinNP00

61552

(597

aa)Cs

cod

ing-syno

nymou

sCn

scoding

-non

syno

nymou

sAminoacid

A-alanineD-aspartic

acidE


-glycineH

-histidineI-iso

leucineL-leu

cineand

M-m

ethion

ineN-

asparagineP-prolin


ineandV-valin

elowastErrorsin

databasesfi

xedNC

notcon

firmed




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of




DLG motif











ETGF motif


77 D (Asp)



79 E (Glu)





82 E (Glu)













6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of








6 Conclusions


Abbreviations




Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of


Disclosure




Acknowledgments


References


























































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of
































































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of
































Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of








Volume 2013

ISRN Anesthesiology


OncologyJournal of


PPARRe sea rch




ISRN Allergy




ObesityJournal of


ISRN Addiction




ISRN AIDS




Volume 2013








ISRN Biomarkers



of

Documents

Genomic Structure and Variation of Nuclear Factor (Erythroid