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Cytotoxic T-Lymphocyte Associated Antigen 4 Gene Polymorphisms and Autoimmune Thyroid Disease: A Meta-Analysis

Clinical and Molecular Epidemiology Unit (F.K.K., J.P.A.I.), Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece; Translational Research Center (T.Ak., H.H.), Kyoto University Hospital, Kyoto University School of Medicine, Kyoto, Japan; Division of Endocrinology and Diabetes (T.Aw., S.Ka., S.Ku.), Department of Medicine, Saitama Medical University, Saitama, Japan; Third Department of Internal Medicine (Yoshiy.B., Yoshio.B.), Showa University School of Medicine, Tokyo, Japan; Department of Pathology (D.A.C.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Department of Hematology (I.F.), Bone Marrow Transplantation and Blood Neoplastic Diseases, Medical Academy, Wroclaw, Poland; Institute of Immunology and Experimental Therapy (I.F., L.K., E.P.), Polish Academy of Sciences, Wroclaw, Poland; Shiraz Institute for Cancer Research (A.G.), Medical School, Shiraz University of Medical Sciences, Shiraz, Iran; Institute of Biomedical Research (S.C.G., J.M.H.), Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham, United Kingdom; Department of Endocrinology (Y.H., I.M.), Kurume University School of Medicine, Kurume, Fukuoka, Japan; Human Molecular Genetics Laboratory of the Department of Forensic Medicine (R.P., M.C.), Departments of Diabetology, Newborn Pathology and Birth Defects, of Medical Genetics, and of Endocrinology (T.B.), Medical University of Warsaw, Warsaw, Poland; Department of Internal Medicine (P.-W.W., R.-T.L.), Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Endocrinology (T.B.), Medical Research Center, Polish Academy of Science, Warsaw, Poland; Department of Molecular Diagnostics (E.I.C.), National Research Center GosNIIgenetika, Moscow, Russia; Graduate Institute of Medical Genetics and Department of Clinical Research (S.-H.H.J.), Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Endocrine and Metabolism Research Center (G.-H.R.O.), Namazee Hospital, Shiraz, Iran; Division of Endocrinology and Metabolism (M.T.), Showa University Fujigaoka Hospital, Yokohama, Kanagawa-ken, Japan; Department of Medical Information (T.T.), Showa University School of Pharmaceutical Science, Tokyo, Japan; Biomedical Research Institute (J.P.A.I.), Foundation for Research and Technology-Hellas, Ioannina, Greece; and Institute for Clinical Research and Health Policy Studies (J.P.A.I.), Department of Medicine, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts

Address all correspondence and requests for reprints to: John P. A. Ioannidis, M.D., Professor and Chairman, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. E-mail: jioannid{at}cc.uoi.gr.

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) per G 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.

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