SNPs in the KCNJ11-ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population

Abstract

Many genetic association studies support a contribution of genetic variants in the KCNJ11-ABCC8 gene locus to type 2 diabetes (T2D) susceptibility in Caucasians. In non-Caucasian populations, however, there have been only a few association studies, and discordant results were obtained. Herein, we selected a total of 31 SNPs covering a 211.3-kb region of the KCNJ11-ABCC8 locus, characterized the patterns of linkage disequilibrium (LD) and haplotype structure, and performed a case-control association study in a Japanese population consisting of 909 T2D patients and 893 control subjects. We found significant associations between eight SNPs, including the KCNJ11 E23K and ABCC8 S1369A variants, and T2D.These disease-associated SNPs were genetically indistinguishable because of the presence of strong LD, as found previously in Caucasians. For the KCNJ11 E23K variant, the most significant association was obtained under a dominant genetic model (OR 1.32, 95% CI 1.09-1.60, P = 0.004). A meta-analysis of East Asian studies, comprising a total of 3,357 T2D patients (77.4% Japanese) and 2,836 control subjects (77.8% Japanese), confirmed the significant role of the KCNJ11 E23K variant in T2D susceptibility. Furthermore, we found evidence suggesting that the KCNJ11 E23K genotype is independently associated with higher blood-pressure levels.

The E23K variation in the KCNJ11 gene is associated with type 2 diabetes in Chinese and East Asian population

“…[1][2][3][4] However, a large-scale association study of these genes has not been carried out in the Chinese Han population; and there was much inconsistency in results in East Asian studies before. [5][6][7][8][9] …”

“…1-4 However, a large-scale association study of these genes has not been carried out in the Chinese Han population; and there was much inconsistency in results in East Asian studies before. [5][6][7][8][9] In this study, 1912 unrelated type 2 diabetes patients and 2041 normal controls (Supplementary methods) were recruited from Shanghai, China, by measuring their clinical characteristics (Supplementary Table 1). Both the SNPs (single nucleotide polymorphisms) mentioned above were genotyped by TaqMan SNP Genotyping Assays on an ABI7900 system (Applied Biosystems, Foster City, CA, USA).…”

“…For meta-analysis, there was no significant heterogeneity (Cochran's Q-test) and publication bias (Egger's test) for rs5219 (P¼0.41 and P¼0.15, respectively) and rs1799854 (P¼0.92 and P¼0.90, respectively). For meta-analysis of the KCNJ11 E23K variant, all eight studies [5][6][7][8][9]11,12 included 7874 cases and 7629 controls and showed a strong significant association (fixed OR 1.15, 95% CI 1.10-1.21, P¼3Â10 À9 , Figure 1a). For the ABCC8 exon16-3t/c variant, all five studies 7,9,13,14 included 4651 cases and 4394 controls and showed no association with type 2 diabetes (fixed OR 1.05, 95% CI 0.99-1.12, P¼0.080, Figure 1b).…”

“…Common polymorphisms in KCNJ11 were detected to be in a strong LD block and the block also extended to the ABCC8 gene in several previous studies; for instance, both ABCC8 S1368A (rs757110) and KCNJ11 rs5215 were in a high level of LD (r 2 40.8) with the E23K variant. 5,7,9 In addition, rs1799854 is located in the 3¢-splice site of the ABCC8 gene and can impair normal splicing. In this study, it is not possible to exclude the ABCC8 gene as a susceptibility gene involved in type 2 diabetes, even though no association was detected for rs1799854 in the East Asian population.…”

Association of the antihypertensive response of iptakalim with KCNJ11 (Kir6.2 gene) polymorphisms in Chinese Han hypertensive patients

“…This study shows that the four KCNJ11 polymorphisms were not related to baseline BP in the hypertensive patients. KCNJ11 polymorphisms were reported to be associated with blood pressure variation and hypertension in the Japanese and Korean population [28][29][30] . Further large scale association studies compared with control subjects are needed to clarify whether these polymorphisms are associated with the pathogenesis of hypertension in Chinese Han population.…”