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

Kazuki Yasuda, Kazuaki Miyake, Yukio Horikawa, Kazuo Hara, Haruhiko Osawa, Hiroto Furuta, Yushi Hirota, Hiroyuki Mori, Anna Jonsson, Yoshifumi Sato, Kazuya Yamagata, Yoshinori Hinokio, He Yao Wang, Toshihito Tanahashi, Naoto Nakamura, Yoshitomo Oka, Naoko Iwasaki, Yasuhiko Iwamoto, Yuichiro Yamada, Yutaka SeinoHiroshi Maegawa, Atsunori Kashiwagi, Jun Takeda, Eiichi Maeda, Hyoung Doo Shin, Young Min Cho, Kyong Soo Park, Hong Kyu Lee, Maggie C.Y. Ng, Ronald C.W. Ma, Wing Yee So, Juliana C.N. Chan, Valeriya Lyssenko, Tiinamaija Tuomi, Peter Nilsson, Leif Groop, Naoyuki Kamatani, Akihiro Sekine, Yusuke Nakamura, Ken Yamamoto, Teruhiko Yoshida, Katsushi Tokunaga, Mitsuo Itakura, Hideichi Makino, Kishio Nanjo, Takashi Kadowaki, Masato Kasuga

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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.

Original languageEnglish
Pages (from-to)1092-1097
Number of pages6
JournalNature Genetics
Volume40
Issue number9
DOIs
StatePublished - 1 Sep 2008

Cite this

Yasuda, K., Miyake, K., Horikawa, Y., Hara, K., Osawa, H., Furuta, H., Hirota, Y., Mori, H., Jonsson, A., Sato, Y., Yamagata, K., Hinokio, Y., Wang, H. Y., Tanahashi, T., Nakamura, N., Oka, Y., Iwasaki, N., Iwamoto, Y., Yamada, Y., ... Kasuga, M. (2008). Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature Genetics, 40(9), 1092-1097. https://doi.org/10.1038/ng.207