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Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus

Nature Genetics 40, 1092–1097 (2008) | Download Citation

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Abstract

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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Acknowledgements

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.

Author information

    • Kazuya Yamagata
    • , He-Yao Wang
    • , Yuichiro Yamada
    • , Yutaka Seino
    •  & Akihiro Sekine

    Present addresses: Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-8556, Japan (K. Yamagata), Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 200031, China (H.-Y.W.), Department of Internal Medicine, Akita University School of Medicine, Akita 010-8543, Japan (Y.Y.), Kansai Electric Power Hospital, Osaka 553-0003, Japan (Y. Seino) and Genome Informatics, Center for Genomic Medicine, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan (A.S.).

Affiliations

  1. Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan.

    • Kazuki Yasuda
    •  & He-Yao Wang

  2. Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

    • Kazuaki Miyake
    • , Yushi Hirota
    • , Hiroyuki Mori
    •  & Masato Kasuga

  3. Department of Diabetes and Endocrinology, Division of Molecule and Structure, Gifu University School of Medicine, Gifu 501-1194, Japan.

    • Yukio Horikawa
    •  & Jun Takeda

  4. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

    • Kazuo Hara
    •  & Takashi Kadowaki

  5. Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan.

    • Haruhiko Osawa
    •  & Hideichi Makino

  6. First Department of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.

    • Hiroto Furuta
    •  & Kishio Nanjo

  7. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden.

    • Anna Jonsson
    • , Valeriya Lyssenko
    •  & Leif Groop

  8. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

    • Yoshifumi Sato
    •  & Kazuya Yamagata

  9. Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.

    • Yoshinori Hinokio
    •  & Yoshitomo Oka

  10. Division of Genetic Information, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.

    • Toshihito Tanahashi
    •  & Mitsuo Itakura

  11. Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Sciences, Kyoto 602-8566, Japan.

    • Naoto Nakamura

  12. Department of Medicine, Diabetes Center, Tokyo Women's Medical University, Tokyo 162-8666, Japan.

    • Naoko Iwasaki
    •  & Yasuhiko Iwamoto

  13. Department of Diabetes and Clinical Nutrition, Kyoto University School of Medicine, Kyoto 606-8501, Japan.

    • Yuichiro Yamada
    •  & Yutaka Seino

  14. Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan.

    • Hiroshi Maegawa
    •  & Atsunori Kashiwagi

  15. Clinical Genome Informatics Center, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.

    • Eiichi Maeda

  16. Department of Genetic Epidemiology, SNP Genetics Inc., Seoul 110-834, Korea.

    • Hyoung Doo Shin

  17. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.

    • Young Min Cho
    • , Kyong Soo Park
    •  & Hong Kyu Lee

  18. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong

    • Maggie C Y Ng
    • , Ronald C W Ma
    • , Wing-Yee So
    •  & Juliana C N Chan

  19. Department of Medicine, Helsinki University Hospital, FIN-00300 Helsinki, Finland.

    • Tiinamaija Tuomi
    •  & Leif Groop

  20. Folkhaelsan Research Center, FIN-00014 Helsinki, Finland.

    • Tiinamaija Tuomi

  21. Department of Clinical Sciences, Medicine Research Unit, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden.

    • Peter Nilsson

  22. Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo 162-8666, Japan.

    • Naoyuki Kamatani

  23. SNP Research Center, Institute of Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan.

    • Akihiro Sekine
    •  & Yusuke Nakamura

  24. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

    • Ken Yamamoto

  25. Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

    • Teruhiko Yoshida

  26. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

    • Katsushi Tokunaga

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Contributions

Principal investigators: K. Yasuda and M.K. Manuscript writing: K. Yasuda., K.M., Y. Horikawa and M.K. Diabetes project planning and design: K. Yasuda, K.M., Y. Hirota, H. Mori, T.Y. and M.K. Ascertainment of study subjects and general data analyses in Japan: K. Yasuda, K.M., Y. Horikawa, K.H., H.O., H.F., Y. Hirota, H. Mori, Y. Sato, K. Yamagata, Y. Hinokio, H.-Y.W., T. Tanahashi, N.N., Y.O., N.I., Y.I., Y.Y., Y. Seino, H. Maegawa, A.K., J.T., E.M., N.K., M.I., H. Makino, K.N., T.K. and M.K. Genotyping and sequencing analyses in Japan: K.M., Y. Horikawa, Y. Hirota, T. Tanahashi, A.S., Y.N., K. Yamamoto, T.Y., K.T. and M.I. Statistical analyses: K.M., Y. Horikawa, Y. Hirota, E.M., T.Y., K.T. and M.I. Genetic analyses in Korea: H.D.S., Y.M.C., K.S.P. and H.K.L. Genetic analyses in Hong Kong: M.C.Y.N., R.C.W.M., W.-Y.S. and J.C.N.C. Genetic analyses in Europe: A.J., V.L., T. Tuomi, P.N. and L.G. Millennium Genome Project Human Genome Variation Team Leader: Y.N. Millennium Genome Project Diabetes Subteam Leader: M.K.

Corresponding author

Correspondence to Masato Kasuga.

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https://doi.org/10.1038/ng.207

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