ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos 10.3892/etm.2012.618 etm-04-03-0538 Articles Association between the CTLA-4 +49A/G polymorphism and Graves’ disease: A meta-analysis SIXIAOYU12 ZHANGXIUFENG1 TANGWENRU12 LUOYING12 Faculty of Environmental Science and Engineering and Laboratory of Molecular Genetics of Aging and Tumor, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China Correspondence to: Dr Ying Luo or Dr Wenru Tang, Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, 727 Jing Ming Nan Road, Chenggong, Kunming, Yunnan 650500, P.R. China, E-mail: yingluo@kmust.edu.cn, E-mail: twr@sina.com 9 2012 20 06 2012 4 3 538 544 31 03 2012 14 06 2012 Copyright © 2012, Spandidos Publications 2012 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

The +49A/G polymorphism of the cytotoxic T-lymphocyte-associated antigen-4 gene (CTLA-4) has been associated with Graves’ disease (GD). However, results have been inconsistent. The aim of this study was to quantitatively summarize the evidence for CTLA-4 +49A/G polymorphism and GD. Electronic search of PubMed was conducted to select studies. Case-control studies containing available genotype frequencies of CTLA-4 +49 were chosen, and Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of this association. Forty-two case-control studies including 8,288 cases and 9,372 controls were identified. Three studies were eliminated from the total 42 studies due to a p-value <0.05 (p-value for Hardy-Weinberg equilibrium in control group) in these studies which induced significant publication bias. The overall results suggested that the variant genotypes were highly associated (p<0.01) with GD risk in all genetic models (additive model: OR, 1.443; 95% CI, 1.319–1.578; p<0.001; recessive model: OR, 1.589; 95% CI, 1.396–1.808; p<0.001; dominant model: OR, 1.621; 95% CI, 1.430–1.837; p<0.001). Similarly, in the subgroup analyses for ethnicity (Caucasian, Asian), the results were positive. This meta-analysis suggests that the CTLA-4 +49A/G polymorphism is highly associated (p<0.01) with increased risk of GD, especially in Caucasians and Asians. To validate this association, further studies with larger participants worldwide are needed to examine associations between this polymorphism and GD.

 cytotoxic T-lymphocyte-associated antigen-4 gene autoimmune thyroid diseases Graves’ disease meta-analysis Introduction

Graves’ disease (GD) is one of the autoimmune thyroid diseases (AITDs) which affect 5% of the general population (1). GD is an autoimmune antibody-mediated, thyroid-specific autoimmune disease which causes thyroid gland tumefaction. GD patients make antibodies to the thyroid-stimulating hormone receptor leading to hyperthyroidism. People of Western countries (∼1.2%) and 0.25–1.09% of people of China are afflicted with GD (2,3). Although environmental factors, such as infection (4) and stress, are very important in the process of Graves’ disease in susceptible individuals, one study in twins revealed that ∼80% of the predisposition to GD is due to genetic factors (5). Several genetic loci have been implicated in the susceptibility to this disease. One of the associated genes is the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene which consists of 4 exons and 3 introns. In 1997, Yanagawa et al (6), Marron et al (7) and Donner et al (8) initially reported that there was an association between CTLA4 and Graves’ disease. The CTLA-4 gene is located on the long arm of chromosome 2q33 and belongs to the immunoglobulin superfamily. Since the CTLA-4 protein transmits an inhibitory signal to T-cells, it has a strong susceptibility in autoimmunity. One of the CTLA-4 gene polymorphisms is located on exon 1 +49, which causes a threonine to alanine substitution in codon 17 (codon 17 T/A). To date, the CTLA-4 +49A/G polymorphism has been studied in different and numerous groups in humans, and a potential association with GD has been found in many results (6–36). However, some results suggest that there is no association between CTLA-4 +49A/G polymorphism and GD (37–46). Thus, the results are still inconsistent. Another problem is that these published studies only refer to a rather modest sample size that limits their significance. Utilizing the advantage of meta-analysis, a powerful method for quantitatively summarizing different study results, we combined the data for analysis and increased the sample size to a reasonable level. In this study, we conducted a meta-analysis to quantitatively assess the effect of the CTLA-4 +49A/G polymorphism on the risk of GD.

 Materials and methods Publication search

PubMed was searched using the terms ‘CTLA 4’, ‘Graves’ and ‘polymorphism’ or ‘CTLA4’, ‘Graves’ and ‘polymorphism’ or ‘cytotoxic T lymphocyte’, ‘Graves’ and ‘polymorphism’ (the last search update was on March 11, 2012). Case-control studies containing available genotype frequencies of 49A/G were chosen. Additional studies were identified by a manual search of the references of the original studies.

 Statistic analysis

For the control group of each study, the observed genotype frequencies of the CTLA-4 +49A/G polymorphism were assessed for Hardy-Weinberg equilibrium using the χ2 test. The strength of association between the +49A/G polymorphism of the CTLA-4 gene and GD was assessed by calculating crude odds ratios (ORs) with 95% confidence intervals (CIs). The pooled ORs were performed for the additive genetic model (G vs. A), dominant model (G/G+G/A vs. A/A) and recessive model (G/G vs. G/A+A/A), respectively. Heterogeneity assumption was checked by a χ2-based Q-test. A p-value of <0.05 for the Q-test indicated a lack of heterogeneity among the studies; the summary OR estimate of each study was calculated by the random effects model (47,48). The potential for publication bias was examined by Begg’s test (funnel plot method) and Egger’s linear regression test (p<0.05 was considered representative of statistical significance) (49). All statistical analyses were performed with Stata software (version 11.0; Stata Corporation, College Station, TX).

 Results Eligible studies

We identified 42 case-control studies concerning the association between the CTLA-4 +49A/G polymorphism and GD, which included 8,288 GD cases and 9,372 controls. These data were used in our meta-analysis (Table I). The distribution of genotypes in the controls of all the studies was in agreement with Hardy-Weinberg equilibrium.

 Meta-analysis

The results of the association between the CTLA-4 +49A/G polymorphism and GD and the heterogeneity test are shown in Table II. The overall results suggest that the variant genotypes were highly associated (p<0.01) with GD risk in all genetic models [additive model: OR, 1.443; 95% CI, 1.319–1.578; p<0.001 (Fig. 1); recessive model: OR, 1.589; 95% CI, 1.396–1.808; p<0.001 (Fig. 2); dominant model: OR, 1.621; 95% CI, 1.430–1.837; p<0.001 (Fig. 3)]. Similarly, in subgroup analyses for ethnicity (Caucasians, Asians), the results were positive.

 Publication bias

Funnel plot and Egger’s test were performed to estimate the publication bias of studies. The results of Egger’s test provided statistical evidence for funnel plot symmetry (for G/G+G/A vs. A/A, p=0.166) (Table II).

 Discussion

This meta-analysis examined the association of the CTLA-4 +49A/G polymorphism with GD and included 8,288 GD cases and 9,372 controls. Three studies were eliminated from the total 42 studies due to a p-value of <0.05 (p-value for Hardy-Weinberg equilibrium in control group) in these studies which induced significant publication bias. The results of Egger’s test provided statistical evidence for funnel plot symmetry (for G/G+G/A vs. A/A, p=0.166). The overall results suggest that the variant genotypes were highly associated (p<0.01) with GD risk in all genetic models (additive model: OR, 1.443; 95% CI, 1.319–1.578; p<0.001; recessive model: OR, 1.589; 95% CI, 1.396–1.808; p<0.001; dominant model: OR, 1.621; 95% CI, 1.430–1.837; p<0.001). Similarly, in subgroup analyses for ethnicity (Caucasians, Asians), the results were positive.

GD is a disease with significant clinical consequences. The mechanism of GD is still relatively unknown. Although environmental factors, such as infection (4) and stress, are important in the process of Graves’ disease in susceptible individuals, one study in twins suggests that ∼80% of the predisposition to GD is due to genetic factors (5). Single nucleotide polymorphisms (SNPs) can be used as a tool for investigating genetic variations and disease susceptibility. GD is an autoimmune antibody-mediated, thyroid-specific autoimmune disease. The CTLA-4 protein can transmit an inhibitory signal to T-cells and has a strong susceptibility in autoimmunity. CTLA-4 protein has recently been described as a gatekeeper of conjugation timing and reduced conjugation may protect against prolonged contact periods of cytotoxic T lymphocytes with autoantigen-defined targets (50). It has been in the centre of attention for its key role in autoimmunity. The +49A/G polymorphism is one of the CTLA-4 three forms of polymorphisms. To date, a multitude of different studies were carried out concerning the association between the CTLA-4 +49A/G polymorphism and GD, but the results are inconsistent. In many studies (6–36) the results are positive, however in others (37–46) the results are negative.

This meta-analysis revealed a highly significant (p<0.01) association between the CTLA-4 +49A/G polymorphism and GD risk, in both Asian and Caucasian subgroups. In conclusion, this meta-analysis suggests that the CTLA-4 +49A/G polymorphism is potentially associated with the risk of GD among Caucasians and Asians. Future, well-designed, large scale studies are necessary to validate this association in different populations.

This work was financially supported by the National Science Foundation of China (nos. 30960152, 30871232, 31170735), the Nature Science Foundation of Yunnan Province (no. 2008C043M) and the Fund of State Key Laboratory of Genetics Resources and Evolution (no. GREKF10-07).

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Forest plot of ORs of the G allele when compared to the A allele (additive model) in the Graves’ patients. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specific weight. The diamond represents the pooled OR and 95% CI. OR, odds ratio; CI, confidence interval.

Forest plot of ORs of the G/G genotype when compared to the A allele carriers (G/A+A/A) (recessive model) in the Graves’ patients. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specific weight. The diamond represents the pooled OR and 95% CI. OR, odds ratio; CI, confidence interval.

Forest plot of ORs of GD G allele carriers (G/G+G/A) when compared to the A/A genotype (dominant model) in the Graves’ patients. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the study-specific weight. The diamond represents the pooled OR and 95% CI. OR, odds ratio; CI, confidence interval.

Distribution of the CTLA-4 +49A/G genotype for patients with Graves’ disease and the controls.

Population Ethnicity or origin Study GD
Control
Year A/A A/G G/G A/A A/G G/G P-valuea
Caucasian South Indian Veeramuthumari et al (9) 2011 11 37 32 29 25 26 0.000819
Asian Thai Kimkong et al (37) 2011 22 49 61 26 73 54 0.875319
Asian Chinese Han Zhao et al (10) 2010 104 730 1030 156 823 945 0.211832
Asian Japanese Kimura et al (11) 2009 62 143 210 142 358 295 0.067982
Caucasian Iranian Khalilzadeh et al (12) 2009 48 43 14 75 25 3 0.606930
Caucasian Iranian Esteghamati et al (13) 2009 114 71 20 75 25 3 0.606930
Others Brazilian Namo Cury et al (38) 2008 43 58 15 39 32 7 0.905523
Asian Chinese Chong et al (14) 2008 7 73 97 24 56 71 0.028090
Asian Taiwanese Wang et al (15) 2007 15 69 124 18 77 97 0.633099
Asian Chinese Zhang et al (16) 2006 2 29 58 7 26 27 0.846451
Caucasian Turkish Tanrikulu et al (17) 2006 48 38 11 42 34 14 0.120930
Asian Chinese Han et al (18) 2006 33 95 135 32 89 75 0.520341
Asian Korean Cho et al (39) 2006 16 112 160 30 197 244 0.240107
Asian Taiwanese Weng et al (40) 2005 8 53 46 15 58 28 0.091603
Caucasian Turkish Sahin et al (19) 2005 29 33 15 43 48 7 0.189953
Caucasian Italian Petrone et al (20) 2005 59 68 23 139 138 24 0.201228
Asian Japanese Iwama et al (41) 2005 17 25 1 78 88 34 0.287293
Asian Taiwanese Wang et al (21) 2004 18 72 81 11 50 87 0.316477
Caucasian Lebanese Nakkash-Chmaisse et al (22) 2004 8 23 3 24 14 0 0.163933
Caucasian Polish Frydecka et al (42) 2004 32 50 17 50 84 20 0.096480
Caucasian White Vaidya et al (23) 2003 88 139 74 146 158 45 0.825642
Asian Japanese Mochizuki et al (24) 2003 1 6 13 12 27 21 0.539129
Caucasian Iranian Kalantari et al (25) 2003 21 49 20 30 53 30 0.510214
Caucasian Polish Bednarczuk et al (26) 2003 75 123 66 77 85 32 0.303455
Asian Japanese Bednarczuk et al (26) 2003 28 140 151 15 63 34 0.093804
Asian Chinese Yung et al (27) 2002 3 54 66 23 59 76 0.046372
Caucasian USA Kouki et al (28) 2002 22 67 31 30 36 14 0.576150
Asian Japanese Kinjo et al (32) 2002 32 62 50 38 46 26 0.107271
Caucasian Tunisian Hadj Kacem et al (30) 2001 31 63 50 26 94 85 0.998814
Caucasian UK Caucasian Allahabadia et al (43) 2001 136 262 86 192 198 34 0.081624
Others African, American, Hispanic, Asian Villanueva et al (44) 2000 42 67 28 53 52 16 0.568526
Asian Korean Park et al (31) 2000 5 35 57 26 75 98 0.061219
Others Not specified Kouki et al (32) 2000 8 29 8 15 23 5 0.390573
Caucasian Moscow Chistyakov et al (33) 2000 6 22 50 25 38 30 0.081864
Others African-American Chen et al (45) 2000 20 25 4 23 19 5 0.718804
Caucasian UK Heward et al (34) 1999 122 192 65 164 171 28 0.067423
Caucasian White Djilali-Saiah et al (46) 1998 23 37 13 47 37 16 0.069793
Caucasian German, Canadian Braun et al (35) 1998 22 56 25 52 48 21 0.096985
Asian Japanese Awata et al (36) 1998 11 44 57 58 197 170 0.938310
Asian Japanese Yanagawa et al (6) 1997 11 64 78 34 88 78 0.287293
Asian Chinese Marron et al (7) 1997 1 11 16 6 39 49 0.632129
Caucasian German, Canadian Donner et al (8) 1997 81 161 63 135 149 41 0.990935

p-value for Hardy-Weinberg equilibrium in the control group. GD, Graves’ disease.

ORs and 95% CI for the CTLA-4 +49A/G polymorphism for different genetic models in patients with Graves’ disease.

Genetic model Population Pooled OR (95% CI) P-value Heterogeneity P-value Begg’s test P-value Egger’s test P-value
Additive (G vs. A) Asian 1.347 (1.203–1.507) <0.001 0.003 0.323 0.373
Caucasian 1.543 (1.324–1.798) <0.001 <0.001 0.426 0.788
Others 1.458 (1.157–1.837) 0.001 0.845 0.174 0.505
Overall 1.443 (1.319–1.578) <0.001 <0.001 0.255 0.642
Recessive (G/G vs. A carriers) Asian 1.476 (1.267–1.721) <0.001 0.003 0.621 0.506
Caucasian 1.770 (1.386–2.260) <0.001 <0.001 0.791 0.586
Others 1.487 (0.931–2.376) 0.097 0.773 0.174 0.275
Overall 1.589 (1.396–1.808) <0.001 <0.001 0.978 0.965
Dominant (G carriers vs. A/A) Asian 1.431 (1.227–1.670) <0.001 0.349 0.187 0.196
Caucasian 1.727 (1.419–2.102) <0.001 <0.001 0.344 0.860
Others 1.739 (1.254–2.412) 0.001 0.850 1.000 0.705
Overall 1.621 (1.430–1.837) <0.001 0.001 0.113 0.166