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Identification of KCNJ15 as a Susceptibility Gene in Asian Patients with Type 2 Diabetes Mellitus |
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| Authors: | Koji Okamoto Naoko Iwasaki Chisa Nishimura Eisei Noiri Miho Takizawa Risa Fujimaki Charlotta Pisinger Torsten Lauritzen Torben Hansen Kazuki Yasuda Kishio Nanjo Masato Kasuga Toshiro Fujita Yasuhiko Iwamoto |
| Institution: | 1 Department of Human Genetics, Graduate School of Tokyo University, Tokyo 113-0033, Japan 2 Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan 3 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan 4 Diabetes Center, Tokyo Women's Medical University, Tokyo 162-8666, Japan 5 Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo 162-8666, Japan 6 Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo 162-8666, Japan 7 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-8666, Japan 8 Hagedorn Research Institute, 2820 Gentofte, Copenhagen, Denmark 9 Research Centre for Prevention and Health, Glostrup University Hospital, 2600 Glostrup, Denmark 10 Steno Diabetes Center, 2820 Gentofte, Copenhagen, Denmark 11 Faculty of Health Sciences, University of Aarhus, 8000 Aarhus, Denmark 12 Department of General Practice, University of Aarhus, 8000 Aarhus, Denmark 13 Faculty of Health Sciences, University of Southern Denmark, 5230 Odense, Denmark 14 Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan 15 Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Ehime 790-8577, Japan 16 First Department of Medicine, Wakayama Medical University, Wakayama 641-8509, Japan 17 Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan 18 Institute of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark |
| Abstract: | 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. |
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