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This version published online on May 13, 2008
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2008-0452
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Submitted on February 27, 2008
Accepted on May 2, 2008

Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan

Yukio Horikawa, Kazuaki Miyake, Kazuki Yasuda, Mayumi Enya, Yushi Hirota, Kazuya Yamagata, Yoshinori Hinokio, Yoshitomo Oka, Naoko Iwasaki, Yasuhiko Iwamoto, Yuichiro Yamada, Yutaka Seino, Hiroshi Maegawa, Atsunori Kashiwagi, Ken Yamamoto, Katsushi Tokunaga, Jun Takeda, and Masato Kasuga*

Department of Diabetes and Endocrinology, Division of Molecule and Structure, Gifu University School of Medicine, Gifu, Japan; Laboratory of Medical Genomics, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan; Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Metabolic Disorder, Research Institute, International Medical Center of Japan; Department of Medical Biochemistry Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Medicine, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan; Department of Internal Medicine, Akita University School of Medicine, Akita, Japan; Kansai Electric Power Hospital, Osaka, Japan; Division of Endocrinology and Metabolism Department of Medicine, Shiga University of Medical Science, Shiga, Japan; Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

* To whom correspondence should be addressed. 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 SNPs within ten 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 fifteen SNPs were genotyped. Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [OR=1.16 (95% 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 regenerative capacity of pancreatic {beta}-cells.

Conclusions: Some of these variants represent common type 2 diabetes-susceptibility genes in both Japanese and Europeans.
Key words: replication • genome-wide association study • type 2 diabetes






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