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Submitted on June 24, 2005
Accepted on December 7, 2005
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka 565-0871, Japan; Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical School; Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital of Medicine and Dentistry; Third Department of Internal Medicine, Interdisciplinary Graduate School of Medical and Engineering, University of Yamanashi; Department of Internal Medicine, Saitama Social Insurance Hospital; Department of Endocrinology and Metabolism, Toranomon Hospital; Department of Internal Medicine, Keio University School of Medicine; Department of Pediatrics, Interdisciplinary Graduate School of Medical and Engineering, University of Yamanashi
* To whom correspondence should be addressed. E-mail: ikegami{at}geriat.med.osaka-u.ac.jp.
Context: Trans-racial 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 multi-center study group in Japan and studied the association of CTLA4 polymorphisms with type 1 diabetes relative to AITD phenotypes.
Subjects: A total of 1837 samples, including 1114 cases (769 with type 1 diabetes and 345 with autoimmune thyroid disease (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 anti-islet 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 sub-classification of type 1 diabetes relative to AITD in genetic studies.
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