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The Association of CTLA4 Polymorphism with Type 1 Diabetes Is Concentrated in Patients Complicated with Autoimmune Thyroid Disease: A Multicenter Collaborative Study in Japan

Department of Geriatric Medicine (H.I., Y.Kaw., T.O.), Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan; Division of Endocrinology and Diabetes, Department of Medicine (T.A., S.K.), Saitama Medical School, Saitama 350-0495, Japan; Department of Metabolism/Diabetes and Clinical Nutrition (E.K.), Nagasaki University Hospital of Medicine and Dentistry, Nagasaki 852-8501, Japan; Third Department of Internal Medicine (T.K., S.T.) and Department of Pediatrics (S.A., M.M.), Interdisciplinary Graduate School of Medical and Engineering, University of Yamanashi, Yamanashi 409-3898, Japan; Department of Internal Medicine (T.M.), Saitama Social Insurance Hospital, Saitama 330-0074, Japan; Department of Endocrinology and Metabolism (K.N.), Toranomon Hospital, Tokyo 105-8470, Japan; and Department of Internal Medicine (A.S., Y.Kan.), Keio University School of Medicine, Tokyo 160-8582, Japan

Address all correspondence and requests for reprints to: Hiroshi Ikegami, M.D., Ph.D., Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: ikegami{at}geriat.med.osaka-u.ac.jp.

Context: Transracial studies are a powerful tool for genetic association studies of multifactorial diseases, such as type 1 diabetes. The low incidence of type 1 diabetes in Asian countries, however, makes it difficult to perform large-scale studies in Asia.

Objective: To overcome this, we have assembled a multicenter study group in Japan and studied the association of CTLA4 polymorphisms with type 1 diabetes relative to autoimmune thyroid disease (AITD) phenotypes.

Subjects: Subjects included a total of 1837 samples, including 1114 cases (769 with type 1 diabetes and 345 with AITD) and 723 control subjects.

Methods: The +6230G>A and +49G>A polymorphisms of CTLA4 as well as HLA-DRB1 and -DQB1 were genotyped.

Results: The +6230G>A polymorphism was significantly associated with type 1 diabetes complicated with AITD (odds ratio, 1.54; P = 0.027) and with AITD alone (odds ratio, 1.31; P = 0.045) but not with type 1 diabetes without AITD. The association with type 1 diabetes positive for autoantibodies to both pancreatic islets and thyroid was particularly strong (odds ratio, 1.87; P = 0.001). Type 1 diabetic patients with the disease-associated GG genotype were characterized by a significantly higher frequency of AITD (P = 0.013), of positivity for both AITD and antiislet autoantibody (P = 0.00086), and of high-risk HLA genotypes (P = 0.034).

Conclusions: Given the high frequency of AITD in patients with type 1 diabetes, these data suggest the possibility that the association of CTLA4 with type 1 diabetes in previous studies may have been secondary to AITD, suggesting the importance of subclassification of type 1 diabetes relative to AITD in genetic studies.

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