We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest P value (6.7 × 10−13, odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 × 10−42 (OR = 1.40; 95% CI = 1.34–1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of β-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
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We thank all the participants in the project; S. Sugano and S. Tsuji for support and helpful discussion throughout the project; H. Sakamoto, K. Yoshimura and N. Nishida for genotyping and quality control of the data; M. Yamaoka-Sageshima, K. Nagase, D. Suzuki and A. Berglund for technical assistance; and staff of Mitsui Knowledge Industry Inc. (Tokyo) for help with bioinformatics. This work was supported by a grant from the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan; a grant from the National Institute of Biomedical Innovation (NIBIO) of Japan; grants from the Ministry of Health, Labour, and Welfare of Japan; a Grant-in-Aid for Scientific Research on Priority Areas (C), “Medical Genome Science (Millennium Genome Project),” “Applied Genomics” and “Comprehensive Genomics” from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and a grant from New Energy and Industrial Technology Development Organization (NEDO). The replication 2 study was supported by a grant from Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER, Tokushima, Japan). The Hong Kong diabetes case-control study was supported by the Hong Kong Research Grants Committee Central Allocation Scheme CUHK 1/04C. The Korean case-control study was supported by a grant from the Korea Health 21 R&D Project of the Ministry of Health and Welfare of the Republic of Korea (00-PJ3-PG6-GN07-001 to K.S.P.). The replication 5 study and Botnia prospective study were supported by Swedish Research Council (Linne grant), Sigrid Juselius Foundation, Folkhaelsan Research Foundation, European Foundation for the Study of Diabetes and Swedish Diabetes Research Foundation.
Supplementary Figures 1–3, Supplementary Tables 1–6, Supplementary Methods (PDF 327 kb)
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