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

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 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.

Introduction of glycated albumin measurement for all blood donors and the prevalence of a high glycated albumin level in Japan

“…It has been reported that the mean BMI of Japanese type 2 diabetes patients is 23.1 kg/m 2 15,16 . There is also a report suggesting that Japanese with a lean constitution might have some susceptibility genes that predispose them to type 2 diabetes mellitus 17 . In fact, the present study showed that the mean BMI of donors with GA ≥16.5% was 24.1 kg/m 2 , a value within the normal range.…”

MYH9 gene polymorphisms may be associated with cerebrovascular blood flow in patients with type 2 diabetes

“…Because MCA is the most common site of cerebrovascular diseases, stenosis of the MCA increased the risk of vascular disease mortality in patients with T2D (Thomas et al, 2008). In our study, rs7903146 of TCF7L2 and rs735853 of MYH9 (Freedman et al, 2009;Cooke et al, 2012) were likely associated with right middle cerebral artery (RMCA) peak blood flow velocity (P = 0.0085, and P = 0.0019, respectively); rs12102171 of SMAD3, rs3746876 of KCNJ15 (Okamoto et al, 2010), rs5753669 of SFI1 (McDonough et al, 2011), and rs13266634 of SLC30A8 (Hu et al, 2009) with RMCA S:D (P = 0.018, 0.011, 0.014, and 0.014, respectively); SNP rs446886 of NUB1 with the left middle cerebral artery (LMCA) mean blood flow velocity (P = 0.01); SNP rs738409 of PNPLA3 with LMCA PI (P = 0.0019); and SNP rs13129697 of SLC2A9 with LMCA S:D (P = 0.029). Many of these associations were moderate; however, several candidate gene SNPs were associated with multiple TCD phenotypes, suggesting weak but detectable contributions to the genetic relative risks of cerebrovascular diseases.…”

Impact of impaired insulin secretion and insulin resistance on the incidence of type 2 diabetes mellitus in a Japanese population: the Saku study

“…Variants in the KCNQ1 gene have been reported to increase the risk of future type 2 diabetes, mostly in Asian individuals [33,34]. The relative risk of type 2 diabetes for Japanese carriers of the KCNJ15 risk allele was 1.76, increasing to 2.54 in individuals with a BMI less than 24 kg/m 2 [35]. These KCNQ1 and KCNJ15 variants have been reported to affect the development of type 2 diabetes by impairing beta cell function [33,34,36,37].…”