TheGenecsofPemphigus DermaThetologicBGenomicEra · DermaThetologicBGenomicEra (TheGenecsofPemphigus! Self/ Animesh A. Sinha, MD, PhD ... Pemphigus Vulgaris Multiple Sclerosis Ulcerative

DermaThe tologic B-‐Genomic Era

The Gene4cs of Pemphigus

Self/

Animesh A. Sinha, MD, PhD

Rita M and Ralph T. Professor of Dermatology Department of Dermatology University at Buffalo

09/17/17

No conflicts

IPPF Newport Beach, CA

•  >100 human autoimmune diseases

•  10-20% of population

•  3rd highest disease burden

Defini'on: Autoimmunity is the failure of an organism to recognize its own cons4tuent parts as "self", which results in an immune response against its own cells and 4ssues.

Autoimmune Disease

Genes

Environment Immune Regula4on

Autoimmune Disease

suscep4bility to disease is COMPLEX

mul'factorial polygenic

Autoimmune Disease

•  Gene4c basis of disease

what is the evidence?

•  Iden4fica4on of disease suscep4bility genes what genes cause disease?

•  Explora4on of func4onal pathways how do genes cause disease?

Gene4cs





Gene4cs

USA Jewish 32 Jews (Jerusalem) 16.1 Greek 9.3 Bulgarian 4.7 Southern Indians 4.4 USA non-‐Jewish 4.2 Malaysian 2.0 Saudi Arabian 1.6 French 1.3 German 0.98 Finnish 0.76

range: 0.76 -‐ 32 per million

Popula4on Incidence per 1x106

Popula4on Studies Gazit and Loewenthal, Autoimmunity Reviews 4:16 (2005) World-‐wide Incidence -‐ PV

Literature: 1.1 : 1 -‐ 2.25 : 1

Sinha study: 2 : 1

Female Predominance in Autoimmune Disease

Gupta et al. Dermatol. Clin. 29(3):393-‐404.

Pemphigus Incidence Worldwide

0 2 4 6 8 10 12 14 16 18

Myasthenia Gravis

Lupus Erythematosus

Vitiligo

Ulcerative Colitis

Type 1 Diabetes

Alopecia Areata

Fibromyalgia

Psoriasis

Rheumatoid Arthritis

Thyroid Disease16 (45.7%)

5 (14.3%)

4 (11.4%)

4 (11.4%)

3 (8.6%)

2 (5.7%)

2 (5.7%)

1 (2.9%)

1 (2.9%)

1 (2.9%)

Autoimmune Co-‐Morbidity

21% of all PV pts report having a co-‐morbid autoimmune diseases

Gupta et al. Dermatol. Clin. 29(3):393-‐404. Sinha study

*

1 (0.6%) 1 (0.6%) 1 (0.6%)

2 (1.2%) 2 (1.2%) 2 (1.2%)

3 (1.8%) 3(1.8%) 3 (1.8%)

4 (2.3%) 5 (2.9%)

6 (3.5%) 7 (4.1%)

9 (5.3%) 9 (5.3%)

10 (5.9%) 13 (7.6%)

25 (14.6%) 27 (15.8%)

0 5 10 15 20 25 30

Autoimmune Hepatitis Scleroderma

Sjorgrens Pemphigus Foliaceous

Fibromyalgia Celiac Disease

Bullous Pemphigoid Alopecia Areata

Thrombopenic Purpura Vitiligo

Pemphigus Vulgaris Multiple Sclerosis Ulcerative Colitis Crohn’s Disease

Lupus Rheumatoid Arthritis

Psoriasis Thyroid Diseases Diabetes - Type I

48% of all PV pa4ents report having one or more rela4ves with autoimmune disease

Autoimmune Disease -‐ Familial Aggrega4on

First Degree 50.6%

Second Degree 34.3%

Third Degree 15.1%

No concordance rates available for monozygo'c vs dyzygo'c twins

Gupta et al. Dermatol. Clin. 29(3):393-‐404. Sinha study

Autoimmune Clusters

Autoimmune Comorbidity

Family History of Comorbidity

Cluster 1 PV AITD RA DM1

Cluster 2 PV AITD RA SLE

Parameswaran A, Sato R, Seiffert-‐Sinha K, Sinha AA (2013) Br J Dermatol 172(3)729-‐38.





Gene4cs

Disease Suscep4bility Genes

•  HLA genes

•  non HLA genes

Inheritance is polygenic


•  HLA genes



Chromosome 6

HLA

Class II Class III Class I

β α α β LMP/TAP β α β β α B C E A G F

HLA

DP DQ

C4 C2Hsp70TNF

DM DR Bf

HLA Gene4c Region

Class II

HLA and PV

> 95% of PV pa4ents type as:

DR4

DR6

Rela4ve Risk (RR) = 15.2 -‐ 127.1

a ra'o of the probability of the disease occurring in the presence of the allele vs in its absence

P1P4 P6 P7 P9

Self/

DR4 DR6 serological

DRB1*0402 DQB1*0503 molecular/ allele

P4 P9 pocket

D70, E71 D57 residue

HLA

HLA II and PV

Sinha et al. A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. Science 239:1026. Todd et al. A molecular basis for MHC class II--associated autoimmunity. Science 240:1003. Sinha et al. Autoimmunity: A failure of self-tolerance. Science 248:1380. Lee et al. Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris. Hum. Immunol. 68(7):630


•  HLA genes



•  candidate gene screen the usual suspects

•  genome wide screen shotgun strategy

genome-‐wide associa4on study (GWAS) next-‐genera4onal sequencing

Strategies to iden'fy risk loci:

non HLA genes

•  IGHC Gibson W et al, Hum Genet 94:675 (1994) 12 pts

•  IGKC no associa'on

•  DSG3 Capon F et al, Clin Lab Invest 154:67 (2005)

•  TNFα, TGFβ, IL-‐10 no associa'on

•  TAP2*C, TAP2*D Slomov E et al, Hum Immunol 66:1213 (2005)

•  PTPN22 no associa'on Sachdev et al, Exp Dermatol 20:514( 2011)

Candidate Gene Screen

*

discovery driven

Sarig et al, J. Invest. Dermatolol. 132:1798 (2012).

Genome Wide Association Studies (GWAS)

Genome Wide Screen

Exome Whole genome

Genome Wide Screen

Next-gen Sequencing





Gene4cs

The Ternary Complex

B Cell

Kera4nocyte

Dsg3 Dsg1

Self/

HLA

T Cell

Pathway to Disease Genes

Environment Immune Regulation

Autoimmune Disease

HLA and PV

HLA-‐ controls

Cytokines é IL-‐1α, IL-‐1β, IL-‐6, IL-‐8, IL-‐13, IL-‐21, IL-‐23, and TNF-‐α

AnBoxidants ê Total anBoxidant capacity (TAC)

AutoanBbodies cluster together based on an4-‐Dsg3, an4-‐TPO, mAChR3, -‐4, -‐5

reac4vity é levels in serum

PV

Gene expression cluster together (unbiased)

HLA+ controls

430

274

110

97

805

119

PV HLA+ CR

HLA-‐driven genes HLA-‐driven genes 1

1. HLA-‐ driven genes

Immune system processes

HLA-‐independent genes 2 -‐

2. HLA-‐independent genes

Cell structural process

Protec4ve genes 3 -‐

3. Protec4ve genes

Biogenesis + metabolic processes

Gene Expression PV blood Microarray experiment – gene chip

AFFYMETRIX HuU133A array

(>54,000 transcripts)

Genetics - Clinical Relevance

•  Iden4fy individuals at risk develop new gene'c screening tests

•  Predict course of disease early interven'on

•  Predict response to therapy tailored therapy •  Understand disease mechanisms new therapeu'c targets

New era of personalized medicine

Innova-on plan: Pa4ent crowd-‐sourced study

Pemphigus Vulgaris – a mobile health perspec4ve

•  Monitor pa4ent condi4on and disease ac4vity in real-‐-me •  Faster data collec4on •  Increased data accuracy •  Photo capable; med log, sleep log, food log

•  New App currently under development in Sinha lab •  Allows user-‐friendly delivery of pa4ent survey •  iOS 9+/Android

•  Ensure secure / HIPAA compliant data transmission

•  Empower pa4ents with resources and care op4ons •  Access to providers, research opportuni4es

Sinha Lab - Leo Pharm

The Sinha Lab

Acknowledgements

Selwyn Chow, MD Amit Sachdev, MD Alvin Coda, MD Veronic Russo, MD Monica Van Acker Maulik Dhanda, MD Razvan Opreanu, MD Jason Smith, PhD Venice Cercado, MD Map Stepanovich, MD Jack Talsma, MD

Ryan Diesler, MD Viola Hysa, MD Megan Olsen, MD Rahgu Ragananthan, MD Erica Lee, MD Carina Rizzo, MD Achim Moesta, PhD Michael Offers, MD

Stephan Stevanovich, PhD Univ Tübingen Sanil Manavalan, MD Columbia University John Gerlach, PhD Michigan State Univ Bill Robinson, MD Stanford University Brian Haab, PhD Van Andel Inst Victor Tong, PhD Univ Singapore

Kris4na Seiffert Sinha, MD Rama Dey-‐Rao, PhD Amit Shah, MD Dhaval Banusali, MD Sreedevi Chintamani, PhD Elizabeth Heller Ankit Gor Tom Sadja Melissa Hoffman Guneet Singh Priya Sansakan Andrew Gaddi

Thank you!!

And remember to donate BLOOD!

PaBents Family members

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TheGenecsofPemphigus DermaThetologicBGenomicEra · DermaThetologicBGenomicEra (TheGenecsofPemphigus! Self/ Animesh A. Sinha, MD, PhD ... Pemphigus Vulgaris Multiple Sclerosis Ulcerative