Letter abstract

Nature Genetics 40, 1092 - 1097 (2008)
Published online: 17 August 2008 | doi:10.1038/ng.207

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

Kazuki Yasuda1, Kazuaki Miyake2, Yukio Horikawa3, Kazuo Hara4, Haruhiko Osawa5, Hiroto Furuta6, Yushi Hirota2, Hiroyuki Mori2, Anna Jonsson7, Yoshifumi Sato8, Kazuya Yamagata8,27, Yoshinori Hinokio9, He-Yao Wang1,27, Toshihito Tanahashi10, Naoto Nakamura11, Yoshitomo Oka9, Naoko Iwasaki12, Yasuhiko Iwamoto12, Yuichiro Yamada13,27, Yutaka Seino13,27, Hiroshi Maegawa14, Atsunori Kashiwagi14, Jun Takeda3, Eiichi Maeda15, Hyoung Doo Shin16, Young Min Cho17, Kyong Soo Park17, Hong Kyu Lee17, Maggie C Y Ng18, Ronald C W Ma18, Wing-Yee So18, Juliana C N Chan18, Valeriya Lyssenko7, Tiinamaija Tuomi19,20, Peter Nilsson21, Leif Groop7,19, Naoyuki Kamatani22, Akihiro Sekine23,27, Yusuke Nakamura23, Ken Yamamoto24, Teruhiko Yoshida25, Katsushi Tokunaga26, Mitsuo Itakura10, Hideichi Makino5, Kishio Nanjo6, Takashi Kadowaki4 & Masato Kasuga2

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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 times 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 times 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 beta-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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  1. Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan.
  2. Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
  3. Department of Diabetes and Endocrinology, Division of Molecule and Structure, Gifu University School of Medicine, Gifu 501-1194, Japan.
  4. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
  5. Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan.
  6. First Department of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
  7. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden.
  8. Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
  9. Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
  10. Division of Genetic Information, Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.
  11. Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Sciences, Kyoto 602-8566, Japan.
  12. Department of Medicine, Diabetes Center, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
  13. Department of Diabetes and Clinical Nutrition, Kyoto University School of Medicine, Kyoto 606-8501, Japan.
  14. Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan.
  15. Clinical Genome Informatics Center, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
  16. Department of Genetic Epidemiology, SNP Genetics Inc., Seoul 110-834, Korea.
  17. Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
  18. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
  19. Department of Medicine, Helsinki University Hospital, FIN-00300 Helsinki, Finland.
  20. Folkhaelsan Research Center, FIN-00014 Helsinki, Finland.
  21. Department of Clinical Sciences, Medicine Research Unit, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden.
  22. Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo 162-8666, Japan.
  23. SNP Research Center, Institute of Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan.
  24. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
  25. Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  26. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
  27. 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.).

Correspondence to: Masato Kasuga2 e-mail: kasuga@med.kobe-u.ac.jp



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