Mol Biol Rep DOI 10.1007/s11033-014-3318-z

Associations between tumor necrosis factor alpha gene polymorphism and sarcoidosis: a meta-analysis Hao Jun Xie • Muli Wu • Yi Niu • Bin Shen Yating Huo • Yuanxiong Cheng



Received: 5 September 2013 / Accepted: 24 February 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract Published studies regarding the association between tumor necrosis factor alpha (TNF-a) gene polymorphism and sarcoidosis risk are inconsistent. In order to clarify this association, we performed a meta-analysis of case–control studies with available data. PubMed, EMBASE and BIOSIS Previews were comprehensively searched to identify relevant studies. Twelve case–control studies in 11 articles involving 3,218 participants were included in the meta-analysis to assess the association between TNF-a gene polymorphism and susceptibility to sarcoidosis. We estimated the pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI) to explore the potential association. Our meta-analysis results suggested that TNF-a-308G/A AA/AG genotype increased sarcoidosis risk, in Asian and Caucasian ethnicity, and in sarcoidosis with Lo¨fgren syndrome. No association was found between TNF-a-238G/A, TNF-a-857C/T polymorphism and sarcoidosis risk. In conclusion, our meta-analysis indicated that AG/GG genotype of TNF-a-308G/A are associated with increased sarcoidosis risk.

Electronic supplementary material The online version of this article (doi:10.1007/s11033-014-3318-z) contains supplementary material, which is available to authorized users. H. J. Xie  Y. Niu  B. Shen  Y. Huo  Y. Cheng (&) Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong, China e-mail: [email protected] M. Wu Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Keywords Sarcoidosis  Tumor necrosis factor alpha  Polymorphism  Meta-analysis

Introduction Sarcoidosis is a systemic disorder of unknown cause which is characterized by its pathological hallmark, the noncaseating granuloma, predominantly affecting the lung [1, 2]. Although the aetiology of sarcoidosis remains unclear, the underlying pathophysiology of the disorder is an antigendriven process, which in genetically susceptible hosts leads to exaggerated immunological response of Th1 type [3]. Among various potential factors contributing to sarcoidosis pathogenesis, one of them is the polymorphisms of TNF-a gene. Granuloma formation in sarcoidosis have been shown to be regulated by numerous endogenous mediators, of which the immunoregulatory cytokine TNF-a is thought to play a important role [4]. Prolonged TNF-a elevation in lung inflammation of chronic sarcoidosis is due to persistent expression of mRNA for TNF-a in macrophages [5]. The human TNF-a gene is located on the chromosomal region 6p21.3–21.1. Several polymorphisms of TNF-a gene have been identified and reported to involve in susceptibility to sarcoidosis. Many studies have investigated the associations between TNF-a gene polymorphisms and sarcoidosis susceptibility. However, previous studies showed controversial results regarding the role of TNF-a polymorphisms in the predisposition and clinical course of sarcoidosis. Therefore, we performed a meta-analysis using published data to assess the association between TNF-a gene polymorphisms and sarcoidosis risk.

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Methods Publication search PubMed, EMBASE and BIOSIS Previews were comprehensively searched (Last search was updated up to May, 2013). The Medical Subject Heading terms and/or text words utilized were ‘sarcoidosis’ or ‘sarcoid’ or ‘Besnier-Boeck-Schaumann disease’ or ‘Besnier-Boeck disease’, and in combination with ‘polymorphism*’ or ‘variant*’ or ‘genetic’ or ‘mutant*’, and in combination with ‘tumor necrosis factor alpha’ or ‘Cachectin-Tumor Necrosis Factor’ or ‘TNF-alpha. No publication language restrictions were imposed. All the searched studies were retrieved, and their references were checked as well for other relevant publications. Inclusion and exclusion criteria Human studies, were included if they met the following criteria: (1) Evaluation of the polymorphisms of TNF-a gene and sarcoidosis risk, (2) Using a case–control design, and (3) Genotype distributions in comparison groups should be available for estimating an ORs with 95 % CI. Studies were excluded if one of the following existed: (1) Not relevant to TNF-a gene polymorphisms or sarcoidosis risk, (2) Design based on family or sibling pairs, and (3) Reviews or abstracts. When more than one of the same patient population was reported in several publications, only the most complete study was included.

polymorphisms were calculated for genotypes AA (TT) versus GG (CC), AG (CT) versus GG (CC), and AA (TT) versus AG (CT), respectively. These pairwise differences were used to determine the most appropriate genetic model. If OR1 = OR3 = 1 and OR2 = 1, a recessive model is indicated. If OR1 = OR2 = 1 and OR3 = 1, a dominant model is indicated. If OR2 = 1/OR3 = 1 and OR1 = 1, a complete overdominant model is indicated. If OR1 [ OR2 [ 1 and OR1 [ OR3 [ 1, or OR1 \ OR2 \ 1 and OR1 \ OR3 \ 1, a codominant model is suggested [7]. Once the best genetic model was identified, this model was used to collapse the three genotypes into two groups (except in the case of a codominant model) and to pool the results. Departure from Hardy–Weinberg equilibrium (HWE) in controls was tested by the Chi square test. Subgroup analyse was performed in terms of ethnicity. The heterogeneity between the studies was assessed by I2 and the Chi square test based Cochrane Q test. A P value [ 0.10 for the Q test indicates a lack of heterogeneity, then the pooled OR estimate of each study was calculated by the fixed effects model. Otherwise, the random effects model was used. Sensitivity analysis was also performed through sequentially excluding individual study. All statistical tests were performed by using the Revman5.2 software (Nordic Cochrane Center, Copenhagen, Denmark), STATA 11.0 software (Stata Corporation, College Station, TX). A P value 0.05 was considered statistically significant, except for test of heterogeneity where a level of 0.10 was used.

Data extraction Results Two investigators (Xie and Wu) independently extracted data from full manuscripts of eligible studies. The following information was collected from each study: first author’s name, year of publication, original country, ethnicity, sample size, sarcoidosis definition, genotyping method, and genotype numbers in cases and controls. Disagreement was resolved by discussion or a third author (Cheng) would assess these articles. Publication bias Publication bias was assessed using funnel plot, and P \ 0.05 was considered statistically significant. Because this method requires a range of studies with varying sizes and subjective judgments, publication bias was also evaluated via Begg’s and Egger’s linear regression test [6]. Statistical analysis ORs and 95 % CIs were used to assess the strength of associations between TNF-a gene polymorphisms and sarcoidosis risk. OR1, OR2, and OR3 regarding TNF-a gene

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Characteristics of included studies As showed in Fig. 1, a total of 12 case–control studies met the inclusion criteria and were thus included in the metaanalysis [8–19]. Of those 12 studies, eleven reported TNF-a308G/A, four studies reported TNF-a-238G/A, two reported TNF-a-857 C/T polymorphism, respectively (Table 1, Table S1). These eligible case–control studies contained 3,218 participants, nine Caucasian, two Asian and one African-American sample populations. The distributions of TNF-a genotypes in normal control were consistent with HWE in all studies (Table 1). In addition, three case–control [8, 17, 19] studies reported TNF-a-308G/A genotypes in sarcoidosis patients with Lo¨fgren’s syndrome, non-Lo¨fgren’s sarcoidosis patients, and normal control, respectively. Meta-analysis of TNF-a gene polymorphism and sarcoidosis We assessed the associations between TNF-a-308G/A polymorphism and sarcoidosis. Of the 11 included case–

Mol Biol Rep Fig. 1 Flow of study identification, exclusion, and inclusion

Table1 Characteristics of the case–control studies included in the meta-analysis First author

Year

Country

Ethnicity

Genotype(II/DI/DD) Case (n) 128

Sarcoidosis definition

Genotyping method

HWE

biopsy-proven

PCR–RFLP

Yes

Control (n)

Kieszko R

2010

Poland

Caucasian

84

Labunski S

2001

Germany

Caucasian

10

27

biopsy-proven

PCR–RFLP

Yes

Makrythanasis, P

2009

Greek

Caucasian

109

212

biopsy-proven

PCR–RFLP

Yes Yes

Mrazek F

2005

Czech

Caucasian

114

232

biopsy-proven

SSP-PCR

Pandey JP A*

2002

USA

African-American

219

219

biopsy-proven

PCR–RFLP

Yes

Pandey JP C*

2002

USA

Caucasian

278

278

biopsy-proven

PCR–RFLP

Yes

Petkovic TR

2013

Serbia

Caucasian

70

50

biopsy-proven

PCR–RFLP

Yes

Seitzer U

1997

Germany

Caucasian

101

216

biopsy-proven

PCR–RFLP

Yes

Seyhan EC Somosko¨vi A

2008

Turkey

Caucasian

90

110

biopsy-proven

PCR–RFLP

Yes

1999

Germany

Caucasian

43

216

biopsy-proven

PCR–RFLP

Yes

Takashige N

1998

Japan

Asian

26

125

biopsy-proven

PCR–RFLP

Yes

Yamaguchi E

2001

Japan

Asian

100

161

biopsy-proven

Sequencing

Yes

A* African–American, C* Caucasian, NA not available, PCR polymerase chain reaction, RFLP restricted fragment length polymorphisms, SSP sequence-specific primers, HWE Hardy–Weinberg equilibrium

control studies, one study maybe the major contributor to heterogeneity and was excluded in quantitative data synthesis [11]. The estimated OR1, OR2 and OR3 in the remaining ten case–control studies were 0.92, 0.77 and 1.0, respectively, and this indicated a dominant model. Overall, significantly increased sarcoidosis risk were found in dominant model (AA/AG vs GG) (Fig. 2). In the subgroup stratified by ethnicity, significantly increased associations were observed in Asian and Caucasian population, but not in African–American population (Fig. 3). We observed a significant association between TNF-a308G/A polymorphism and Lo¨fgren’s syndrome sarcoidosis patients in dominant model (AA/AG vs GG). No such

associations was found between TNF-a-308G/A polymorphism and non-Lo¨fgren’s sarcoidosis patients (Fig. 4). In addition, we also performed meta-analysis for TNFa-238G/A and TNF-a-857C/T polymorphism, but neither of them was found to be associated with sarcoidosis risk. Sensitivity analysis and publication bias In order to assess the reliability of our results, we performed a sensitivity analysis by sequentially excluding individual study. Statistically similar results were obtained after sequentially excluding each study. Publication bias was assessed by funnel plot. The shape of the funnel plot

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Mol Biol Rep Fig. 2 Odds ratios (ORs) for associations between TNF-a308 G/A polymorphism and sarcoidosis risk in overall studies. The sizes of the squares indicate the relative weight of each study. Bars, 95 % confidence interval (CI)

Fig. 3 Odds ratios (ORs) for associations between TNF-a-308 G/A polymorphism and sarcoidosis risk among different ethnicities The sizes of the squares indicate the relative weight of each study. Bars, 95 % confidence interval (CI).

showed slightly asymmetric (Fig. 5). However, neither Egger’s test nor Begg’s test indicated significant publication bias (P = 0.078 and P = 0.283, respectively).

Discussion Sarcoidosis is a multisystem granulomatous disease of unknown cause, characterized by the formation of lymphocytes, mononuclear phagocytes and epithelioid cell granuloma in the affected organs [20, 21]. The current hypothesis of its aetiology is that it occurs in genetically susceptible people exposed to specific but unknown

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environmental agents [21]. A particular inclination for certain ethnic groups supports the assumption that genetic factors play an important role in the onset of the disease [1, 21]. Therefore, identification of specific gene loci will probably be important in delineating the pathogenesis of sarcoidosis. Recently, evidence for genetic susceptibility of sarcoidosis was comprehensively reviewed, and a major association has been suggested between sarcoidosis and the TNF-a gene polymorphisms [22]. However, the results of published studies on the association of the TNF-a gene polymorphisms with sarcoidosis were inconsistent. Therefore, we performed this meta-analysis to clarify this relationship.

Mol Biol Rep Fig. 4 Odds ratios (ORs) for associations between TNF-a308 G/A polymorphism and sarcoidosis risk (considering Lo¨fgren syndrome). A TNF-a308G/A polymorphism and Lo¨fgren’s syndrome sarcoidosis patients; B NF-a-308G/ Apolymorphism and nonLo¨fgren’s syndrome sarcoidosis patients. The sizes of the squares indicate the relative weight of each study. Bars, 95 % confidence interval (CI). LS, Lo¨fgren syndrome. NLS, non-Lo¨fgren syndrome

Fig. 5 Funnel plot of publication bias Funnel plot with pseudo 95 % confidence limits was used (AA/AG vs GG)

Our meta-analysis suggested that TNF-a-308 AA/AG genotype is associated with increased sarcoidosis risk. This is consistent with a previous meta-analysis [23] and further confirms the hypothesis that subject carriers of the variant in TNF-a-308G/A polymorphism confers susceptibility to sarcoidosis. In addition, in subgroup stratified by ethnicity, TNF-a-308 AA/AG genotype increased sarcoidosis risk in both Asian and Caucasian population. Moreover, we also observed a significant association between TNF-a-308G/A polymorphism and Lo¨fgren’s syndrome sarcoidosis patients, but no such associations found for non-Lo¨fgren’s sarcoidosis patients. Finally, neither TNF-a-238G/A nor TNF-a-857C/T polymorphisms was found to be associated with sarcoidosis risk. Lo¨fgren’s syndrome was defined as the association of erythema nodosum, periarticular ankle inflammation, or both with unilateral or bilateral hilar or right paratracheal adenopathy, with or without pulmonary involvement in sarcoidosis [24]. Three case–control studies reported genotypes of TNF-a-308G/A polymorphism in sarcoidosis patients with Lo¨fgren’s syndrome, non-Lo¨fgren’s

sarcoidosis patients, and normal control, respectively [8, 17, 19]. We performed meta-analysis with data in these studies, and found a significant association between TNFa-308G/A polymorphism and Lo¨fgren’s syndrome sarcoidosis patients, but not for non-Lo¨fgren’s sarcoidosis patients. However, this result should be interpreted with caution due to a small number of studies. In order to advance the understanding of immunopathogenesis of sarcoidosis, more studies should be designed to analyze the TNF-a gene genotypes distribution in sarcoidosis patients considering gender, organ affected, and the type of presentation (Lo¨fgren and non-Lo¨fgren syndrome) in the future. Several strengths in our meta-analysis could be listed as follows. First of all, we have comprehensively searched several databases with explicit and systematic search strategies. In addition, the results of this study did not show obvious publication bias. Furthermore, after excluding one study [11] that might cause significant heterogeneity, no obvious heterogeneity between studies was observed in overall and subgroup analyses. Thus, publication bias and heterogeneity did not seem to have influenced the results. Finally, in sensitivity analysis, there was little modification after sequentially excluding individual study, suggesting the reliability of our meta-analysis results. Our meta-analysis should be interpreted with caution due to some inevitable limitations. Firstly, twelve published studies fulfilled our selection criteria, thus the metaanalysis was restricted to a moderate sample size primarily comprising subjects from Caucasian population, with only five studies for TNF-a-238 G/A, three for TNF-a-857 C/T, four for Lo¨fgren and non-Lo¨fgren syndrome assessment, respectively. Secondly, most of the studies included in our meta-analysis were performed in Asians and Caucasians. Thus, our results may be applicable only to these ethnic groups. Thirdly, sarcoidosis itself is a complex and

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multifactorial disease and potential interactions among gene–gene and gene-environment should be considered. In conclusion, our study indicated that TNF-a-308 AA/ AG genotype increased sarcoidosis risk, both in Asian and Caucasian ethnicity, and in sarcoidosis with Lo¨fgren syndrome, but not in those without Lo¨fgren syndrome. No association was found between TNF-a-238 G/A, TNF-a857 C/T and sarcoidosis. However, further larger samples studies in different populations, with more detailed individual data are needed to confirm our results. Acknowledgments This study was supported by a research grant from Natural Science Foundation of Guangdong Province (No. s2012010009036). Conflict of interest

None.

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Associations between tumor necrosis factor alpha gene polymorphism and sarcoidosis: a meta-analysis.

Published studies regarding the association between tumor necrosis factor alpha (TNF-α) gene polymorphism and sarcoidosis risk are inconsistent. In or...
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