Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus.
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 beta 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 x 10(-7), odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76-3.67) and with unstratified T2DM (p = 6.7 x 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 beta 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.
Okamoto
Koji
K
Department of Human Genetics, Graduate School of Tokyo University, Japan.
Iwasaki
Naoko
N
Nishimura
Chisa
C
Doi
Kent
K
Noiri
Eisei
E
Nakamura
Shinko
S
Takizawa
Miho
M
Ogata
Makiko
M
Fujimaki
Risa
R
Grarup
Niels
N
Pisinger
Charlotta
C
Borch-Johnsen
Knut
K
Lauritzen
Torsten
T
Sandbaek
Annelli
A
Hansen
Torben
T
Yasuda
Kazuki
K
Osawa
Haruhiko
H
Nanjo
Kishio
K
Kadowaki
Takashi
T
Kasuga
Masato
M
Pedersen
Oluf
O
Fujita
Toshiro
T
Kamatani
Naoyuki
N
Iwamoto
Yasuhiko
Y
Tokunaga
Katsushi
K
D000328:Adult; D000368:Aged; D044466:Asian People; D016022:Case-Control Studies; D002891:Chromosomes, Human, Pair 21; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology*
C103861:KCNJ15 protein, human; D024661:Potassium Channels, Inwardly Rectifying