Association between the CTLA-4 +49A/G polymorphism and Graves' disease: A meta-analysis

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.