Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: A meta-analysis

Context: Cytotoxic T-lymphocyte associated antigen 4 (CTLA- 4) polymorphisms have been widely examined for their associations with autoimmune thyroid diseases [Graves' disease (GD) and Hashimoto thyroiditis (HT)], but their relative population effect remains unclear. Objective: The aim was to generate large-scale evidence on whether the CTLA-4 polymorphisms (A49G and CT60) and haplotypes thereof increase the susceptibility to GD and/or HT. Design, Setting, and Participants: Meta-analyses of group-level data were reviewed from 32 (11,019 subjects) and 12 (4,479) published and unpublished studies for the association of the A49G polymorphism with GD and HT, respectively (PubMed and HuGeNet search until July 2006). There were 15 (n = 7246) and six (n = 3086) studies available for the CT60 polymorphism, respectively. Meta-analyses of individual-level data from 10 (4906 subjects) and five (2386) collaborating teams for GD and HT, respectively, were also reviewed. Main Outcome Measures: Association of gene variants and haplotypes with GD and HT was measured. Results: Group-level data suggested significant associations with GD and HT for both A49G [odds ratios 1.49 (P = 6 x 10(-14)) and 1.29 (P = 0.001) perG allele, respectively] and CT60 [1.45 ( P = 2 x 10(-9)) and 1.64 (P = 0.003) per G allele, respectively]. Results were consistent between Asian and Caucasian descent subjects. Individual-level data showed that compared with the AA haplotype, the risk conferred by the GG haplotype was 1.49 (95% confidence interval 1.31,1.70) and 1.36 (95% confidence interval 1.16,1.59) for GD and HT, respectively. Data were consistent with a dose- response effect for the G allele of CT60. Conclusion: The CT60 polymorphism of CTLA-4 maps an important genetic determinant for the risk of both GD and HT across diverse populations.