TY - JOUR
T1 - Identification of KCNJ15 as a Susceptibility Gene in Asian Patients with Type 2 Diabetes Mellitus
AU - Okamoto, Koji
AU - Iwasaki, Naoko
AU - Nishimura, Chisa
AU - Doi, Kent
AU - Noiri, Eisei
AU - Nakamura, Shinko
AU - Takizawa, Miho
AU - Ogata, Makiko
AU - Fujimaki, Risa
AU - Grarup, Niels
AU - Pisinger, Charlotta
AU - Borch-Johnsen, Knut
AU - Lauritzen, Torsten
AU - Sandbaek, Annelli
AU - Hansen, Torben
AU - Yasuda, Kazuki
AU - Osawa, Haruhiko
AU - Nanjo, Kishio
AU - Kadowaki, Takashi
AU - Kasuga, Masato
AU - Pedersen, Oluf
AU - Fujita, Toshiro
AU - Kamatani, Naoyuki
AU - Iwamoto, Yasuhiko
AU - Tokunaga, Katsushi
N1 - Funding Information:
The Danish study was supported by the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care and the Danish Diabetes Association. The Inter99 study was supported by the Danish Research Council; the Danish Centre for Health Technology Assessment of Novo Nordisk Inc.; the Research Foundation of Copenhagen County; the Ministry of Internal Affairs and Health; the Danish Heart Foundation; the Danish Pharmaceutical Association; the Augustinus Foundation; the Ib Henriksen Foundation; the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe, and South Jutland; together with the Danish Research Foundation for General Practice; the Danish Centre for Evaluation and Health Technology Assessment; the Diabetes Fund of the National Board of Health; the Danish Medical Research Council; the Aarhus University Research Foundation; and the Novo Nordisk Foundation.
Funding Information:
This study was supported by a grant-in-aid for scientific research in the priority area “Comprehensive Genomics” from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) to K.T. This study was partially supported by the BioBank Japan Project on the Implementation of Personalized Medicine, MEXT (E.N.); a Health and Labor Sciences research grant for research on the human genome; grants for tissue engineering and food biotechnology from the Ministry of Health, Labour and Welfare of Japan (E.N.); Special Coordination Funds for Promoting Science and Technologies, MEXT (E.N.); the Satake Takako Award from Tokyo Women's Medical University; the Lilly Award from the Japan Diabetes Society; a Grant-in-aid for Scientific Research, MEXT (N.I.); and a grant-in-aid for scientific research in the priority area “Medical Genome Science,” MEXT (N.I. and K.T.).
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2009.12.009
DO - 10.1016/j.ajhg.2009.12.009
M3 - Article
C2 - 20085713
AN - SCOPUS:73149110158
VL - 86
SP - 54
EP - 64
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -
