Identification of KCNJ15 as a Susceptibility Gene in Asian Patients with Type 2 Diabetes Mellitus

Koji Okamoto, Naoko Iwasaki, Chisa Nishimura, Kent Doi, Eisei Noiri, Shinko Nakamura, Miho Takizawa, Makiko Ogata, Risa Fujimaki, Niels Grarup, Charlotta Pisinger, Knut Borch-Johnsen, Torsten Lauritzen, Annelli Sandbaek, Torben Hansen, Kazuki Yasuda, Haruhiko Osawa, Kishio Nanjo, Takashi Kadowaki, Masato KasugaOluf Pedersen, Toshiro Fujita, Naoyuki Kamatani, Yasuhiko Iwamoto, Katsushi Tokunaga

研究成果: Article査読

45 被引用数 (Scopus)

抄録

Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the β cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 × 10-7, odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76-3.67) and with unstratified T2DM (p = 6.7 × 10-6, OR = 1.76, 95% CI = 1.37-2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic β cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians.

本文言語English
ページ(範囲)54-64
ページ数11
ジャーナルAmerican Journal of Human Genetics
86
1
DOI
出版ステータスPublished - 2010
外部発表はい

ASJC Scopus subject areas

  • 遺伝学
  • 遺伝学(臨床)

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