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Association Studies of Variants in the Genes Involved in Pancreatic ß-Cell Function in Type 2 Diabetes in Japanese Subjects

¹ Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
² Division of Health and Preventive Medicine, Department of Lifelong Sport, Biwako Seikei Sport College, Shiga, Japan
³ Department of Endocrinology, Diabetes and Rheumatology, Division of Bioregulatory Medicine, Gifu University School of Medicine, Gifu, Japan
⁴ Department of Clinical Laboratory Medicine, Wakayama University of Medical Science, Wakayama, Japan
⁵ First Department of Medicine, Wakayama University of Medical Science, Wakayama, Japan
⁶ Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe, Japan
⁷ Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
⁸ Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube, Japan
⁹ Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
¹⁰ Division of Cell Replacement and Regenerative Medicine, Medical Research Institute, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan
¹¹ Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
¹² Department of Internal Medicine, Hikone Municipal Hospital, Shiga, Japan
¹³ Departments of Medicine and Human Genetics, University of Chicago, Chicago, Illinois

Address correspondence and reprint requests to Susumu Seino, Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, Japan. E-mail: seino{at}med.kobe-u.ac.jp

Abbreviations: HWE, Hardy-Weinberg equilibrium; K_ATP channel, ATP-sensitive K⁺ channel; LD, linkage disequilibrium; SNP, single nucleotide polymorphism

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic ß-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2–2, NKX6–1, and NEUROD1) and genes encoding the ATP-sensitive K⁺ channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 –3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97–1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.

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