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Insulin Gene/IDDM2 Locus in Japanese Type 1 Diabetes: Contribution of Class I Alleles and Influence of Class I Subdivision in Susceptibility to Type 1 Diabetes

Division of Endocrinology and Diabetes, Department of Medicine (T.A., S.Ku., M.O., S.Ka.) and Division of RI Laboratory, Biomedical Research Center (T.A., H.Ii.), Saitama Medical University, Saitama 350-0495, Japan; Department of Metabolism/Diabetes and Clinical Nutrition (E.K., M.U.), Nagasaki University Hospital of Medicine and Dentistry, Nagasaki 852-8501 Japan; Department of Endocrinology, Diabetes and Metabolism (H.Ik., Y.Kaw.), Kinki University School of Medicine, Osaka 589-8511, Japan; Third Department of Internal Medicine (T.K., S.T.), Interdisciplinary Graduate School of Medicine 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 160-8582, 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: Takuya Awata, Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan. E-mail: awata{at}saitama-med.ac.jp.

Context: It is suggested that insulin autoimmunity plays an important role in the development of type 1 diabetes in humans. However, the association between insulin gene (INS) region (IDDM2) and type 1 diabetes has been uncertain in Asians.

Objective: A multicenter collaboration study was conducted to clarify the role of the IDDM2 region in Japan.

Subjects and Methods: In total, 661 patients with type 1 diabetes and 706 control subjects were enrolled. The INS variable number of tandem repeat (VNTR) class I/class III status was estimated by genotyping the –23 HphI single nucleotide polymorphism. From surrounding polymorphisms across the insulin gene, we also inferred haplotypes bearing INS VNTR lineages.

Results: The frequency of the class I allele was 99.3% in patients and 96.7% in controls (P < 10^–5), and the class I/III or III/III genotype was found in 1.4% of patients and in 6.4% of controls [odds ratio (OR) 0.20, P < 10^–5]. The class I subdivision revealed IC to increase significantly in patients with type 1 diabetes (P = 0.002), whereas ID did not; the distribution of IC and ID was significantly different between patients and controls (P = 0.014).

Conclusion: The present study certainly shows that the IDDM2 region is also a susceptibility locus in the Japanese population. Furthermore, it was revealed that IC may be more susceptible to type 1 diabetes than ID, which could be evidence that the INS VNTR itself confers susceptibility to type 1 diabetes.