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SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations

Nature Genetics volume 40, pages 1098–1102 (2008)Cite this article

Abstract

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 × 10−12; OR = 1.26, 95% CI = 1.18–1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 × 10−9; OR = 1.32, 95% CI = 1.20–1.45, rs2237897, P = 6.8 × 10−13; OR = 1.41, 95% CI = 1.29–1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 × 10−3; OR = 1.14, rs2237897, P = 2.4 × 10−4; OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 × 10−11; OR = 1.24, rs2237897, P = 1.2 × 10−4; OR = 1.36).

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Figure 1: Schematic view of the association of type 2 diabetes with the variants in the KCNQ1 region.

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Acknowledgements

We thank all participating doctors and staff from collaborating institutes for providing DNA samples. We also thank the technical staff of the Laboratory for Endocrinology and Metabolism at the Center for Genomic Medicine for providing technical assistance. This work was partly supported by a grant from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan. The Danish study was supported by Lundbeck Foundation Centre of Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LUCAMP), the European Union (EUGENE2, grant no. LSHM-CT-2004-512013) and the Danish Medical Research Council. Funding for Singapore arm of the study was supported by the National Medical Research Council (NMRC/1115/2007). We thank the staff of National Healthcare Group Polyclinics and National University of Singapore for their contributions towards the establishment of the Singapore Diabetes Cohort Study.

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Authors and Affiliations

  1. Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Hiroyuki Unoki & Shiro Maeda

  2. Laboratory for Statistical Analysis, Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Atsushi Takahashi & Naoyuki Kamatani

  3. Laboratory for Medical Informatics, Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Takahisa Kawaguchi & Tatsuhiko Tsunoda

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

    Kazuo Hara, Momoko Horikoshi & Takashi Kadowaki

  5. Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Copenhagen, Denmark

    Gitte Andersen, Johan Holmkvist, Knut Borch-Johnsen, Torben Hansen & Oluf Pedersen

  6. Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Daniel P K Ng & Siti Nurbaya

  7. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, 2600, Denmark

    Knut Borch-Johnsen, Torben Jørgensen & Oluf Pedersen

  8. Faculty of Health Science, University of Aarhus, Aarhus, 8000, Denmark

    Knut Borch-Johnsen

  9. Department of General Practice, University of Aarhus, Aarhus, 8000, Denmark

    Annelli Sandbæk & Torsten Lauritzen

  10. Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Kanagawa, Japan

    Michiaki Kubo

  11. Diabetes Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan

    Tetsuya Babazono & Yasuhiko Iwamoto

  12. Health Center, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Hiroshi Hirose

  13. Department of Internal Medicine, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Matsuhiko Hayashi

  14. Department of Medicine, Shiga University of Medical Science, Otsu, 520-2192, Shiga, Japan

    Atsunori Kashiwagi & Ryuichi Kikkawa

  15. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, 701-0192, Okayama, Japan

    Kohei Kaku

  16. Department of Medicine, Metabolism and Endocrinology, School of Medicine, Juntendo University, Tokyo, 113-8421, Japan

    Ryuzo Kawamori

  17. Department of Endocrinology, Singapore General Hospital, Singapore, 169608, Singapore

    E Shyong Tai

  18. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan

    Yusuke Nakamura

Authors
  1. Hiroyuki Unoki
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  2. Atsushi Takahashi
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  3. Takahisa Kawaguchi
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  4. Kazuo Hara
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  6. Gitte Andersen
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  7. Daniel P K Ng
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  27. Takashi Kadowaki
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  28. Ryuichi Kikkawa
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  29. Yusuke Nakamura
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  30. Shiro Maeda
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Contributions

Principal investigators: S.M., H.U., Y.N. BioBank project planning and design: Y.N. Collected subjects and participated in the diagnostic evaluations: K.H., M. Horikoshi, T.B., H.H., M. Hayashi, Y.I., A.K., K.K., R. Kawamori, T. Kadowaki, R. Kikkawa. Oversaw a genotyping: M.K. Wrote the paper: S.M., H.U., Y.N., O.P. Statistical analyses: A.T., T. Kawaguchi, T.T., N.K. Principal investigator for Singapore study: D.P.K.N. Singapore study: S.N., E.S.T. Principal investigator for Danish study: O.P. Danish study: G.A., J.H., K.B.-J., T.J., A.S., T.L., T.H.

Corresponding author

Correspondence to Shiro Maeda.

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Unoki, H., Takahashi, A., Kawaguchi, T. et al. SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40, 1098–1102 (2008). https://doi.org/10.1038/ng.208

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