Infection, Genetics and Evolution 12 (2012) 1473–1480

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Infection, Genetics and Evolution

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SP110 gene polymorphisms and tuberculosis susceptibility: A systematic reviewand meta-analysis based on 10 624 subjects

Xun Lei a, Hang Zhu a, Lang Zha b, Yang Wang a,⇑a School of Public Health and Health Management, Chongqing Medical University, Chongqing 400016, Chinab Department of Gastrointestinal Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

a r t i c l e i n f o a b s t r a c t

Article history:Received 4 April 2012Received in revised form 12 May 2012Accepted 25 May 2012Available online 9 June 2012

Keywords:SP110PolymorphismTuberculosisSusceptibilityMeta-analysis

1567-1348/$ - see front matter � 2012 Elsevier B.V. Ahttp://dx.doi.org/10.1016/j.meegid.2012.05.011

⇑ Corresponding author. Address: School of Publicment, Chongqing Medical University, No.1 YixueyuChongqing 400016, China. Tel./fax: +86 23 68485008

E-mail address: wy525023@yahoo.com.cn (Y. Wan

Tuberculosis (TB), caused by infection of Mycobacterium tuberculosis, is a major challenge to global publichealth. The SP110 (Speckled 110) gene, which is considered as a host genetic susceptibility to TB, has beenwidely studied in recent years, yet the results were somewhat contradictory and indeterminate. Wesystematically searched published literatures on SP110 polymorphisms and tuberculosis risk until Janu-ary 2012 in relevant databases, selected studies by previously defined criteria, extracted key data andquantitatively summarized associations of the most extensively studied polymorphisms through meta-analysis. A total of 10 624 subjects from seven case-control studies were included in the present study.In overall meta-analysis, pooled odds ratio of polymorphisms rs1135791, rs9061, rs11556887,rs3948464, rs1346311 were 1.01 (95% CI: 0.71–1.44), 0.86 (95% CI: 0.70–1.04), 0.99 (95% CI: 0.67–1.47), 1.29 (CI: 0.89–1.89) and 0.95 (CI: 0.86–1.04) respectively; the summary odds ratio of sensitivityanalysis specifically on pulmonary TB were 1.02 (95% CI: 0.65–1.54) for rs1135791, 0.84 (95% CI: 0.68–1.02) for rs9061, 0.88 (95% CI: 0.57–1.36) for rs11556887, 0.94 (95% CI: 0.85–1.04) for rs1346311; andin the ethnicity stratified analysis, the estimated odds ratio were 0.97 (95% CI: 0.54–1.73) forrs1135791 and 0.86 (95% CI: 0.70–1.04) for rs9061 among Asians. None of the target polymorphismsin SP110 gene observed in the present quantitative synthesis was detected to be significantly associatedwith TB susceptibility. Given the moderate strength of the results, the complexities of pulmonary andextra-pulmonary host genetic polymorphisms, gene-gene and gene-environment interactions, and thecross-species difference between human and mice, it would not be robust to remark that SP110 has norole in TB progress.

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1. Introduction

Tuberculosis (TB) remains a leading cause of death and beingconsidered the number one killer among infectious diseases(Russell et al., 2010). According to the report from the WorldHealth Organization, about 9 million new cases arise and eventu-ally 2 million die of this disease annually, most of whom occur inthe developing countries (Jassal and Bishai, 2010). One-third pop-ulation worldwide is estimated to infect with Mycobacterium tuber-culosis (WHO, 2010), but only 10% of those will evolve clinicdisease, which suggests that genetic factors are inherently involvedin the pathophysiology of TB (Bellamy, 2005).

The SP110 (Speckled 110) gene is considered as one of promis-ing candidates for regulate susceptibility to M. tuberculosis infec-tion, since it is the closest human homologue of the mouse gene

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.g).

Ipr1 (intracellular pathogen resistance-1), which locates at thesst1 (super-susceptibility to tuberculosis 1) locus on chromosome1 and has been demonstrated to essentially determine resistanceto pulmonary TB in a murine model (Kramnik, 2008; Pan et al.,2005). The SP110 gene (51 037 bp on 2q37.1; MIM 604457) is acomponent of cellular structures called nuclear bodies (Blochet al., 2000). The SP110 nuclear body protein (also known as tran-scriptional coactivator SP110 or interferon-induced protein 41/75),which is encoded by SP110 gene, probably mediate interactionsbetween hosts and pathogens by participating in transcriptionalactivation in macrophages in response to intracellular pathogens(Nicewonger et al., 2004; North and Jung, 2004).

Therefore, epidemiological studies were conducted to deter-mine this genetic risk factor to TB. In 2006, Kerrie Tosh et al. firstlyreported that SP110 gene were related to TB in West Africansadopting a family-based study design (Tosh et al., 2006), and somemore studies followed in different study designs from then on.However, the findings of them were inconsistent, partly due toinadequate statistical power, selection bias or population diversity.Thus we performed the present systematic review and meta-anal-

1474 X. Lei et al. / Infection, Genetics and Evolution 12 (2012) 1473–1480

ysis on most extensively studied SNPs of SP110 (rs1135791,rs9061, rs11556887, rs3948464, rs1346311), to provide a moreprecise and comprehensive estimation of the association betweenSP110 gene and human TB susceptibility.

2. Methods

2.1. Search strategy

Studies published prior to the end of January 2012 were identi-fied through a search of Cochrane Library, PubMed, Embase, Ovid,ISI Web of Knowledge, Chinese BioMedical Literature (CBM), VIPDatabase for Chinese Technical Periodicals, WangFang Data, usingboth the MeSH terms and free terms words ‘SP110’ or ‘gene’ or‘polymorphism’, in combination with ‘tuberculosis’ or ‘TB’; we alsoperformed a manual search of citations, conference abstracts, andthe bibliographies of expert advisors.

2.2. Selection criteria

Two reviewers (Lei X, Zhu H) screened all the retrieved litera-tures and citations by title/abstract and then full texts. Inclusioncriteria were: (1) case–control studies presenting original data onthe associations between SP110 polymorphisms and TB; (2) studiesdirectly calculate the odds ratios (OR), or offer the size of the sam-ples, distribution of alleles, genotypes, or other sufficient data toinfer the results; (3) the most recent papers with the largest pop-ulation were included when multiple publications reported onthe same or overlapping data (Little et al., 2002); (4) publicationlanguage was limited to English and Chinese. Exclusion criteriawere: (1) family-based study design with linkage considerations;(2) TB Patients with other disease (HIV or diabetes); (3) publicationtypes as news, letter, editorial, comment, review, conference sum-mary or bibliography.

2.3. Data extraction

Two reviewers (Lei X, Zhu H) independently extracted key infor-mation from eligible studies through a pre-specified extractingform, discussed on disagreements and reached a consensus forall items. A third intercessor was involved when necessary. Foreach study, data was collected concerning the first author and yearof publication; characteristics of the study design and subjects(study size, ethnicity and country, mean age, male proportion, TBdiagnosis, HIV status, source of controls and matching criteria);distribution and frequency of alleles and genotypes for each poly-morphism among cases and controls; deviation from Hardy–Wein-berg equilibrium (HWE) in control subjects.

2.4. Quality evaluation

Two reviewers (Lei X, Zhu H) independently assessed each eligi-ble article according to a pre-designed evaluation form based onthe STREGA (STrengthening the REporting of Genetic Associationstudies) (Little et al., 2009)and CASP (Critical Appraisal Skills Pro-gramme) for case-control study (CASP, 2011), which contained ele-ven items associated with valid data reported in the study. For eachitem there are fair degrees to record a ‘‘yes’’ (scored 2), ‘‘can’t tell’’(scored 1) or ‘‘no’’ (scored 0), and a total score from 0 to 22. Studieswould be divided into three grades (A, B or C) due to evaluationcriteria and their scores: Grade A (scored 15–22) if it is of highquality, credible and there are no factors which have strong impacton outcomes; Grade B (scored 8–14) if it is of medium quality andthere are some unknown factors; Grade C (scored 0–7) if it is ofinferior quality and there are factors which severely influence the

credibility of the research outcome. Only the studies of Grade Aor B would be included in the final synthesis.

2.5. Statistical analysis

Odds ratios (OR) with corresponding 95% confidence intervals(CI) for alleles and genotypes comparing cases with controls wereused to estimate the association between SP110 gene polymor-phism and TB risk. The Heterogeneity assumption was checkedby chi-square based Q-test and I-squared test. The heterogeneitywas not considered significant when I2 < 50%, and the pooled ORestimate of the each study could be calculated by the fixed effectsmodel (Mantel–Haenszel method) (Schmidt et al., 2009). Other-wise, the random effects model (DerSimonian & Laird method)was adopted (DerSimonian and Kacker, 2007). HWE was examinedin controls by asymptotic Pearson’s chi-square test for each poly-morphism among studies (Olson and Foley, 1996), as cases maynot be in HWE if there was indeed an association between geno-type and disease outcome (Schaid and Jacobsen, 1999). Sensitivityanalyses were performed after excluding studies specifically onextra-pulmonary TB, or restricting the analysis specifically on pul-monary TB (Tobias, 1999). Stratified analyses were conducted withrespect to the host ethnicity when enough studies (at least three)were included for a certain population (Pike et al., 1980). An esti-mate of possible publication bias was statistically assessed by theBegg rank correlation method and Egger weighted regression test(p < 0.05 was considered indicative of statistically significant pub-lication bias) (Egger et al., 1997). All statistical tests were per-formed through STATA software package (version 11.0, CollegeStation, TX). The p value of 0.05 for any test or model was consid-ered to be statistically significant.

3. Results

3.1. Eligible studies

A total of 281 publications were achieved by literature search.Among those 93 were publications excluded after overlap checkingbetween the databases, 159 were excluded by title and abstractscreening, and 23 were excluded through detailed full-text exam-ination, among those three (Tao et al., 2008; Zhou et al., 2008;Xiong et al., 2008) were excluded because they appeared to usethe same subjects data in another study from the same authorsteam (Cong et al., 2010), which was included as it was the most re-cent publication by these authors. Fig. 1 revealed the whole screen-ing process and main exclusion reasons.

We finally identified seven studies from six articles published(five in English and one in Chinese), from 2006 to 2011, involvinga total of 4 847 TB cases and 5 777 controls (Abhimanyu et al.,2011; Babb et al., 2007; Cong et al., 2010; Liang et al., 2011; Szesz-ko et al., 2007; Thye et al., 2006). Studies were conducted in a widerange of geographical settings, with 49.2% of cases of African, 39.4%of European descent and 11.4% of Asian.

Table 1 presented the main characteristics and data of includedstudies. All of these studies were related to the pulmonary tuber-culosis (PTB) except one was for lymph node tuberculosis (LNTB)(Abhimanyu et al., 2011b). The sample sizes ranged from 220 to4370. Most cases were diagnosed by the acid-fast bacilli on sputumsmear and confirmed by M. tuberculosis on sputum culture. None ofHIV-positive cases was included. Controls were mainly comprisedof healthy populations matched in gender, age, ethnicity and resi-dence status. All studies were categorized into grade A (scoredfrom 16 to 19) in the quality evaluation.

The number of relevant SNPs tested in eligible studies werefrom eight to nearly thirty (not particularly presented), and five

Fig. 1. Flow diagram of the study identification process.

X. Lei et al. / Infection, Genetics and Evolution 12 (2012) 1473–1480 1475

most widely investigated SNPs of the SP110 gene were selected forpooled analysis to test the associations between SP110 polymor-phisms and tuberculosis susceptibility: four studies aboutrs1135791 (g.47552 T > C) with 2 033 subjects (Cong et al., 2010;Babb et al., 2007; Abhimanyu et al., 2011; Liang et al., 2011), fourstudies about rs9061 (g.12718 G > A) with 1 415 subjects (Conget al., 2010; Abhimanyu et al., 2011; Liang et al., 2011), four studiesabout rs11556887 (g.7013 C > T) with 5 171 subjects (Szeszkoet al., 2007; Abhimanyu et al., 2011; Liang et al., 2011), four studiesabout rs3948464 (g.33974 C > T) with 5 152 subjects (Cong et al.,2010; Babb et al., 2007; Szeszko et al., 2007; Abhimanyu et al.,2011), four studies about 1346311 (g.2302 C > T) with 6 503 sub-jects (Thye et al., 2006; Szeszko et al., 2007; Abhimanyu et al.,2011). Table 2 summarized the absolute numbers of allele frequen-cies in cases and controls. The genotype distribution in all controlshad been tested and found to be in the HWE.

3.2. Quantitative data synthesis

The relationship between five SNPs of SP110 gene and tubercu-losis risk was explored through a quantitative synthesis of sevenstudies involved 10 624 subjects.

Fig. 2A shows the association between SP110 rs1135791 poly-morphism and TB. Meta-analysis suggested that allele T might

not a risk factor for TB with a pooled OR of 1.01 (95% CI: 0.71–1.44) as compared to the allele C (allele contrast of T vs. C) in over-all. The random effects analysis was adopted because of heteroge-neity among studies (p = 0.017; I2 = 70.7%). No significantpublication bias was found by Begg rank correlation analysis(p = 0.734) and Egger weighted regression analysis (p = 0.297). Sen-sitivity analysis was conducted without a study which detected thelymph node tuberculosis (LNTB) genetic risk (Fig. 2B), and no sig-nificant association between rs1135791 variant and the pulmonarytuberculosis (PTB) was found with a summary OR of 1.02 (95% CI:0.65–1.54). We further performed a stratified analysis among Asiansubjects, the synthesised result revealed no evident associationwith TB susceptibility for Asian individuals (OR = 0.97, 95% CI:0.54–1.73) (Fig. 2C). Since lack of enough study data, the geneticrisk to TB for non-Asian subjects was not examined by stratifiedanalysis.

Good homogeneity was observed among studies addressingrs9061 polymorphism (p = 0.565; I2 = 0), thus the fixed effectsmodel was adopted for meta-analysis. During the data synthesis,we found no significant association between rs9061 variant andTB susceptibility for the allele contrast of G vs. A (OR = 0.86, 95%CI: 0.70–1.04), see Supplementary Fig. S1A. No substantial publica-tion bias was observed by Begg rank correlation analysis(p = 0.308) and Egger weighted regression analysis (p = 0.391).

Tabl

e1

Char

acte

rist

ics

ofth

ein

divi

dual

stud

ies

incl

uded

wit

hpo

lym

orph

ism

sof

the

SP11

0ge

ne.

Stu

dyre

fere

nce

Popu

lati

onSa

mpl

esi

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ses/

con

trol

s

Mal

epa

tien

ts(%

)M

ean

age

(yea

r)M

eth

odof

case

diag

nos

isC

ontr

olso

urc

eQ

ual

ity

grad

e

Cas

esC

ontr

ols

Liet

al.(

2011

),Li

ang

etal

.(2

011)

Ch

ines

e30

8/62

852

.940

.5±

17.5

37.4

±13

.8PT

B(H

IV-)

.Cli

nic

ally

and

X-r

aydi

agn

osed

,AFB

and

cult

ure

sco

nfi

rmed

Blo

oddo

nor

s,cl

inic

ally

nor

mal

,no

TBh

isto

ries

,TST

-,X

-ray

-A

(sco

red

19)

Abh

iman

yuet

al.

(201

1)a

Nor

thIn

dian

110/

78N

Ac

34(1

8–70

)28

(21–

65)

PTB

(HIV

-).C

lin

ical

lyan

dX

-ray

diag

nos

ed,A

FBan

dcu

ltu

re-c

onfi

rmed

.No

imm

un

osu

ppre

ssiv

epr

esen

tati

ons

Hea

lth

y,ra

ndo

mly

chos

ense

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dag

e-m

atch

edst

ude

nts

and

labo

rato

rype

rson

nel

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sign

s,sy

mpt

oms,

orh

isto

ryof

prev

iou

sm

ycob

acte

rial

infe

ctio

n

A(s

core

d18

)

Abh

iman

yuet

al.

(201

1)b

Nor

thIn

dian

32/7

8N

A25

(18–

49)

As

abov

eon

edLN

TB.fi

ne-

nee

dle

aspi

rati

oncy

tolo

gy,c

ult

ure

sco

nfi

rmed

As

abov

eon

eA

sab

ove

one

Thye

etal

.(2

006)

Wes

tA

fric

an20

04/2

366

NA

NA

33.6

(6–6

0)PT

B(H

IV-)

.Sym

ptom

s,ph

ysic

alex

amin

atio

n,

ches

tx

ray,

spu

tum

smea

r,cu

ltu

re-c

onfi

rmed

Un

rela

ted

pers

onal

con

tact

sof

pati

ents

and

com

mu

nit

ym

embe

rsfr

omn

eigh

bori

ng

hou

ses.

Mat

chin

gw

ith

pati

ents

for

sex

and

age

A(s

core

d16

)

Szes

zko

etal

.(2

007)

Ru

ssia

n19

12/2

104

73.8

43.8

(17–

86)

30(1

6–66

)PT

B(H

IV-)

.TB

con

tact

,cli

nic

alsy

mpt

oms,

X-r

ays

and

spu

tum

smea

rpo

siti

ve,c

ult

ure

-con

firm

edLo

cal

hea

lth

ypo

pula

tion

,adu

ltbl

ood

ban

kdo

nor

sw

ith

no

his

tory

ofTB

A(s

core

d19

)

Bab

bet

al.

(200

7)So

uth

Afr

ican

381/

417

5437

32PT

B(H

IV-)

.Mic

robi

olog

ical

lyco

nfi

rmed

From

sam

eet

hn

ican

dso

cioe

con

omic

grou

p,h

ealt

hy,

no

his

tory

ofTB

A(s

core

d16

)

Con

gJi

ann

iet

al.(

2010

)C

hin

ese

100/

106

6838

.98

±14

.71

37.4

2±

10.7

8PT

B(H

IV-)

.X-r

ays

and

spu

tum

smea

rpo

siti

ve,

cult

ure

-con

firm

edH

ealt

hy

popu

lati

onco

llec

ted

bylo

cal

hos

pita

lan

dC

DC

,no

his

tory

ofTB

and

oth

erch

ron

icdi

seas

eA

(sco

red

18)

aD

ata

from

this

stu

dyis

rela

ted

toth

epu

lmon

ary

tube

rcu

losi

s(P

TB).

bD

ata

from

this

stu

dyis

rela

ted

toth

ely

mph

nod

etu

berc

ulo

sis

(LN

TB).

cN

A=

not

avai

labl

e.d

Dat

ain

this

box

isth

esa

me

wit

hab

ove

stu

dy.

1476 X. Lei et al. / Infection, Genetics and Evolution 12 (2012) 1473–1480

Likewise we conducted a sensitivity analysis specifically on PTB bydeleting the study about LNTB (Fig. S1B), and the result was notmaterially altered (OR = 0.84, 95% CI: 0.68–1.02). As all the suffi-cient data came from four studies of Asians, the result of associa-tion between rs9061 variant and TB risk could represent thestratified analysis for Asian subjects (OR = 0.86, 95% CI: 0.70–1.04).

We found no significant susceptibility to TB associated with thevariant at the rs11556887 locus by the allele contrast of C vs. T(OR = 0.99, 95% CI: 0.67–1.47), see Supplementary Fig. S2A. Sub-stantial heterogeneity was observed among studies (p = 0.007;I2 = 75.2%), therefore we adopted the random effects model formeta synthesis. Accordingly, the Begg rank correlation analysis(p = 0.100) and Egger weighted regression analysis (p = 0.83) indi-cated no significant publication bias existed. Sensitivity analysisparticularly on PTB still revealed it was not obviously associatedwith rs11556887 variant (OR = 0.88, 95% CI: 0.57–1.36)(Fig. S2B). For lack of sufficient data, stratified analyses were notconducted for different host ethnicities.

No evident association was found between rs1346311 variantand TB susceptibility with a summary OR of 0.95 (CI: 0.86–1.04)by the fixed effects model, since the medium homogeneity amongstudies (p = 0.114; I2 = 49.6%), see Supplementary Fig. S3A. No sub-stantial publication bias was found (p = 0.296 for Begg rank corre-lation analysis; p = 0.324 for Egger weighted regression analysis).The sensitivity analysis particularly on PTB caused no significantchange while excluding the study about LNTB (OR = 0.94, 95% CI:0.85–1.04) (Fig. S3B). Necessary information from different ethnic-ities was not obtained for stratified analyses.

Fig. S4 illustrates the result of meta-analysis on the associationbetween rs3948464 variant and TB risk. It suggested rs3948464polymorphism might not be a factor of TB susceptibility with apooled OR of 1.29 (CI: 0.89–1.89) trough the random effects anal-ysis (p = 0.001; I2 = 73.9%). No significant publication bias wasfound by Begg rank correlation analysis (p = 0.308) and Eggerweighted regression analysis (p = 0.208). Data extracted from in-cluded studies were not sufficient to conduct the sensitivity anal-ysis on PTB and stratified analyses with ethnicities.

4. Discussion

Only a minority of individuals will develop to clinical disease,even if infected with M. tuberculosis (Schluger, 2001). Besides theenvironmental factors such as poor economic conditions, malnutri-tion, stress and overcrowding, the variability in the human geneswhich control host defense is thought to partly contribute to theinter-individual variability of clinical outcome (Bellamy, 2005;Hoal, 2002). Many candidate genes, including SP110 (Tosh et al.,2006), SLC11A1(NRAMP1) (Bellamy et al., 1998; Liaw et al., 2002),IFNG (Bream et al., 2000; Vallinoto et al., 2010), NOS2A (Gomezet al., 2007; Velez et al., 2009), HLA (Goldfeld et al., 1998; Raviku-mar et al., 1999), VDR (Roth et al., 2004), P2RX7 (Li et al., 2002;Sharma et al., 2010), TLR (Velez et al., 2010), CCL2 (Feng et al.,2011), IL10 (Oral et al., 2006; Shin et al., 2005)and so on, have beenreported to be involved in human TB susceptibility. SP110 gene isthe closest human homologue of the Ipr1, which was confirmedto be associated with PTB susceptibility through mice experiments(Pan et al., 2005). This gene is the second TB susceptibility candi-date found by using inbred mouse strains, the other being SLC11A,which has proved to be related to human TB risk (Li et al., 2011).SP110 is speculated to probably mediate an interaction amongthe nuclear hormone receptor, interferon signal transmission andpathogens, subsequently impact the appearance and progress ofTB disease after mycobacterium infection (North and Jung, 2004).Many researchers have studied on TB risk resulted from SP110 vari-ants, however, the conclusions were somewhat inconsistent (Tosh

Table 2Allele frequencies (given in absolute number, cases vs. controls) of the individual studies.

Study reference rs1135791 rs9061 rs11556887 rs3948464 rs1346311

T C G A C T C T C T

Li et al. (2011), Liang et al. (2011) 516/963 98/261 481/987 131/223 533/1141 59/73 NA NA NA NAAbhimanyu et al. (2011)a NAc NA 48/48 172/108 183/126 37/30 17/10 203/146 204/139 16/17Abhimanyu et al. (2011)b 40/97 24/59 15/33 49/123 49/101 15/55 NA NA 63/139 1/17Thye et al. (2006) NA NA NA NA NA NA NA NA 1577/2007 391/489Szeszko et al. (2007) NA NA NA NA 3297/3584 483/576 3409/3733 371/407 3259/3634 525/528Babb et al. (2007) 537/578 225/256 NA NA NA NA 562/608 200/226 NA NACong et al. (2010) 155/181 45/31 149/170 51/42 NA NA 191/180 9/32 NA NA

a Data from this study is related to the pulmonary tuberculosis (PTB).b Data from this study is related to the lymph node tuberculosis (LNTB).c NA = not available.

X. Lei et al. / Infection, Genetics and Evolution 12 (2012) 1473–1480 1477

et al., 2006; Cong et al., 2010; Babb et al., 2007; Abhimanyu et al.,2011). In order to adjust biases and avoid limitations from individ-ual studies, we performed a systematic review and meta-analysis,based on literature identification until 10 January 2012, to summa-rize associations between TB susceptibility and target SP110 poly-morphisms, which are rs1135791 (g.47552 T > C) located in exon13, rs9061 (g.12718 G > A) located in exon 5, rs11556887 (g.7013C > T) located in exon 4, rs3948464 (g.33974 C > T) located in exon11, rs1346311 (g.2302 C > T) located in intron 1 of SP110 generespectively, their general loci are shown in Fig. 3.

During our meta-analysis, we found none of five target SNPshad a statistically significant association with TB in overall popula-tion, with estimated OR (95% CI) of 1.01 (95% CI: 0.71–1.44), 0.86(95% CI: 0.70–1.04), 0.99 (95% CI: 0.67–1.47), 1.29 (CI: 0.89–1.89)and 0.95 (CI: 0.86–1.04) respectively. Likewise, no significant asso-ciations were detected in polymorphisms rs1135791, rs9061,rs11556887 and rs1346311 through sensitivity analysis, whileleaving out the study on LNTB and restricting the analysis specifi-cally on pulmonary TB, although sometimes the I-square value de-creased and better homogeneity was observed (for rs11556887and rs1346311), which suggested that SP110 variants at thesepolymorphisms might not be significantly related with the devel-opment of pulmonary TB. Otherwise, this unchanged result maycome from the less weight of the LNTB study in statistical synthesisbecause of its relatively small sample size.

We also conducted the stratified analysis by ethnicity to mini-mize the heterogeneity from different human species. However,available data among included studies can just form a subgroupmeta-analysis of Asian population, and we found no significantassociation between TB risk and rs1135791 (OR = 0.97, 95% CI:0.54–1.73) or rs9061 (OR = 0.86, 95% CI: 0.70–1.04) for Asians. Itis noteworthy that two studies from China both with the subjectsof Chinese Han ethnicity, one of which claimed rs1135791 geno-type C/T could increase TB risk (OR = 1.98, 95% CI: 1.11–3.52) (Conget al., 2010) while the other revealed it seemed to be a protectingfactor for TB (OR = 0.61, 95% CI: 0.45–0.82) (Liang et al., 2011). Thisdeviation may result from geographic diversity (the former in thewest vs. the latter in the east of China), sample size (206 vs. 936)or experiment conditions. For other ethnicities, the number of in-cluded study were less than three, which was considered as thelower limit for data synthesis due to the case-control study designwith moderate statistical power. Therefore subgroup meta-analy-sis was not performed on other populations. Nevertheless, wemay also find clues from previous epidemiologic studies. KerrieTosh et al. reported three polymorphisms in SP110 were associatedwith TB in Gambia, Republic of Guinea and Guinea-Bissau of WestAfrica through family-based studies (Tosh et al., 2006), in contra-diction however, no association was detected in a larger case-con-trol study in the South African population (Babb et al., 2007), andthe negative result was validated in another case-control studies

done by Thye T et al. using Ghana samples (Thye et al., 2006). Thisdeviation may be caused by different study designs, populations, orsubjects ages, as participants in family-based studies tend to beyounger than those in case-control studies (Schurr and Kramnik,2008).

The results of Begg rank correlation method and Egger weightedregression test suggest no obvious publication bias existing witheach SP110 polymorphism in the present meta-analysis. However,publication bias may potentially not be detected since the numberof finally included studies was relatively small (n = 7), and it is pos-sible that unpublished articles, such as scientific dissertations, maybe missed because only published studies can be involved in ourstudy.

Moreover, two factors should be considered when interpretingthe statistical results: (1) whether the allele is in linkage disequi-librium with the true disease-causing variant, and (2) whetherthe association is a false-negative result (type II error) (Hoffjanet al., 2003; Silverman and Palmer, 2000). Some studies found thatthe five SNPs were in linkage disequilibrium (Cong et al., 2010;Thye et al., 2006; Szeszko et al., 2007; Abhimanyu et al., 2011;Liang et al., 2011), which suggests that the results are thereforenot independent. All the polymorphisms loci in our study are inHWE in control groups, which may minimize type II error, thatis, the association between the variants and susceptibility to TBin our meta-analysis may not be false-negative results.

There are also some limitations that may affect the presentconclusions. First, heterogeneity found to exist in our study is apotential influence when interpreting any results gained bymeta-analyses. Second, original studies meeting with our inclusioncriteria are relatively few, and not all necessary information couldbe obtained from included studies, thus more detailed sub-group-ing analysis of TB types or ethnicities could not be well performed.Third, the sample sizes of some included studies are rather small,which may reduce their statistical power. Fourth, SP110 gene con-tains many more polymorphisms than those mentioned in thisarticle. Due to the limited evidence available on other polymor-phisms, the present review was restricted to only five most widelystudied polymorphisms. Furthermore, included studies were lim-ited to those published in English or Chinese which may induce po-tential bias into data analysis to some extent.

5. Conclusions

From the combination results of currently relevant studies, ourstudy suggest that SP110 gene polymorphisms at rs1135791,rs9061, rs11556887, rs3948464 and rs1346311 are not signifi-cantly associated with TB susceptibility during overall analyses,sensitivity analyses and stratified analyses. We performed thepresent study through a strict approach of systematic review and

Fig. 2. Association between rs1135791 T/C polymorphism and risk of TB infection in overall (A) and Asian (C) populations, and risk of PTB infection (B). The estimated oddsratio and 95% confidence interval were pooled through the random effects model (DerSimonian & Laird method).

Fig. 3. Figure Sketch map of the five gene loci in the SP110 variant. rs1346311: In1 g.2302 C > T (at �745 of the ATG); rs11556887: Ex4 g.7013 C > T [p.Val128Ala]; rs9061:Ex5 g.12718 G > A [p.Glu207Lys]; rs3948464: Ex11 g.33974 C > T [p.Ser425Leu]; rs1135791: Ex 13 g.47552 T > C [p.Met523Thr].

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meta-analysis, which has been recognized as an effective methodto solve inconsistence and deviation of clinical questions throughreviewing and summarizing the previously published original re-searches. In spite of this, considering the biological function ofSP110 in the induction of apoptosis, which is validated to be asso-ciated with TB development for its mouse homologous gene Ipr1,the cross-species variant could be a potential influence factor wheninterpret the inconsistent results between human and mice (Kram-nik, 2008; Pan et al., 2005); and not all SNPs of SP110 were involvedin our study, perhaps, it would be not robust enough to remark thatSP110 has no role in TB progress due to moderate-evidenced con-clusion in the present study. Well-designed epidemiological stud-ies with large sample size among different ethnicities on bothpulmonary and extra-pulmonary TB are necessary, which shouldalso consider gene-gene and gene-environment interactions, tocontinually provide and update reliable data for a comprehensiveand definite conclusion.

Conflict of Interest

The authors declare that they have no competing interests.

Acknowledgement

This study was not supported by any funds.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.meegid.2012.05.011.

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