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Replication of Genome-Wide Association Studies of Type 2 Diabetes Susceptibility in Japan

Department of Diabetes and Endocrinology (Y.Ho., M.E., J.T.), Division of Molecule and Structure, Gifu University School of Medicine, Gifu 501-1194, Japan; Laboratory of Medical Genomics (Y.Ho.), Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan; Division of Diabetes, Metabolism and Endocrinology (K.M., Y.Hir., M.K.), Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Metabolic Disorder (K.Yas.), Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan; Department of Metabolic Medicine (K.Yamag.), Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan; Division of Molecular Metabolism and Diabetes (Y.Hin., Y.O.), Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan; Department of Medicine (N.I., Y.I.), Diabetes Center, Tokyo Women’s Medical University, Tokyo 162-8666, Japan; Department of Diabetes and Clinical Nutrition (Y.Y., Y.S.), Kyoto University School of Medicine, Kyoto 606-8501, Japan; Division of Endocrinology and Metabolism Department of Medicine (H.M., A.K.), Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Molecular Genetics (K.Yamam.), Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; and Department of Human Genetics (K.T.), Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Address all correspondence and requests for reprints to: Masato Kasuga, Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: kasuga{at}med.kobe-u.ac.jp.

Background: In Europeans and populations of European origin, several groups have recently identified novel type 2 diabetes susceptibility genes, including FTO, SLC30A8, HHEX, CDKAL1, CDKN2B, and IGF2BP2, none of which were in the list of functional candidates.

Objective and Design: The aim of this study was to replicate in a Japanese population previously identified associations of single nucleotide polymorphisms (SNPs) within 10 candidate loci with type 2 diabetes using a relatively large sample size: 1921 subjects with type 2 diabetes and 1622 normal controls.

Results: A total of 15 SNPs were genotyped. Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [odds ratio (OR) = 1.16 (95% confidence interval (CI) 1.05–1.27); P = 4.5 x 10^–3] in SLC30A8; rs1111875 [OR = 1.27 (95% CI 1.14–1.40); P = 1.4 x 10^–5] and rs7923837 [OR = 1.27 (95% CI 1.13–1.43); P = 1.0 x 10^–4] in HHEX; rs10811661 [OR = 1.27 (95% CI 1.15–1.40); P = 1.9 x 10^–6] in CDKN2B; rs4402960 [OR = 1.23 (95% CI 1.11–1.36); P = 8.1 x 10^–5] and rs1470579 [OR = 1.18 (95% CI 1.07–1.31); P = 8.3 x 10^–4] in IGF2BP2; and rs7754840 [OR = 1.28 (95% CI 1.17–1.41); P = 4.5 x 10^–7] and rs7756992 [OR = 1.27 (95% CI 1.15–1.40); P = 9.8 x 10^–7] in CDKAL1. The first and second strongest associations were found at variants in CDKAL1 and CDKN2B, both of which are involved in the regenerative capacity of pancreatic β-cells.

Conclusion: Some of these variants represent common type 2 diabetes-susceptibility genes in both Japanese and Europeans.

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