An Exploratory Study of the Association between KCNB1 rs1051295 and Type 2 Diabetes and Its Related Traits in Chinese Han Population

Abstract

Since the KCNB1 encoding Kv2.1 channel accounts for the majority of Kv currents modulating insulin secretion by pancreatic islet beta-cells, we postulated that KCNB1 is a plausible candidate gene for genetic variation contributing to the variable compensatory secretory function of beta-cells in type-2 diabetes (T2D). We conducted two studies, a case-control study and a cross-section study, to investigate the association of common single-nucleotide polymorphisms (SNPs) in KCNB1 with T2D and its linking traits. In the case-control study, we first examined the association of 20 tag SNPs of KCNB1 with T2D in a population with 226 T2D patients and non-diabetic subjects (screening study). We then identified the association in an enlarged population of 412 T2D patients and non-diabetic subjects (replication study). In the cross-sectional study, we investigated the linkage between the candidate SNP rs1051295 and T2D by comparing beta-cell function and insulin sensitivity among rs1051295 genotypes in a general population of 1051 subjects at fasting and after glucose loading (oral glucose tolerance tests, OGTT) in 84 fasting glucose impaired subjects, and several T2D-related traits. We found that among the 19 available tag SNPs, only the KCNB1 rs1051295 was associated with T2D (P = 0.027), with the rs1051295 TT genotype associated with an increased risk of T2D compared with genotypes CC (P = 0.009). At fasting, rs1051295 genotype TT was associated with a 9.8% reduction in insulin sensitivity compared to CC (P = 0.008); along with increased plasma triglycerides (TG) levels (TT/CC: P = 0.046) and increased waist/hip (W/H) ratio (TT/CC: P = 0.013; TT/TC: P = 0.002). OGTT confirmed that genotype TT exhibited reduced insulin sensitivity by 16.3% (P = 0.030) compared with genotype TC+CC in a fasting glucose impaired population. The KCNB1 rs1051295 genotype TT in the Chinese Han population is associated with decreased insulin sensitivity and increased plasma TG and W/H ratio, which together contribute to an increased risk for T2D.

Association of KCNB1 polymorphisms with lipid metabolisms and insulin resistance: a case-control design of population-based cross-sectional study in Chinese Han population

“…rs1051295: Compared with genotype CC, both of genotype TT ( P = 0.03, b = 0.06 (0.01, 0.12)) and TC ( P = 0.10, b = 0.10(-002, 0.22)) was associated or inclined to be associated with increased serum TG levels, in line with our previous report [ 2 ]. We also found that genotype TT tended to be associated with increased BMI ( P = 0.09, b = -0.22 (-0.48, 0.04)), HOMA-IR ( P = 0.09, b = 0.04(-0.01, 0.09)), FINS ( P = 0.11, b = 2.92(-0.06, 0.65)) and HOMA-B ( P = 0.09, b = 5.66(-0.86, 12.18)) compared with genotype CC (Table 1 ).…”

“…Our recently reported case–control study in Chinese Han population showed a strong association of KCNB1 rs1051295 genotype TT with an increased risk of becoming afflicted with metabolic syndrome leading to T2D. Specifically, we showed the genotype TT of this SNP was associated with several metabolic traits of metabolic syndrome, including increased waist to hip ratio (WHR), fasting insulin (FINS) levels, increased serum triglyceride (TG) levels, and decreased insulin sensitivity at basal condition [ 2 ].…”

“…In β-cells, these Kv2.1-SNARE complex interactions can enhance insulin secretion [ 6 ]. To our knowledge, there have been no in vivo or in vitro studies to demonstrate a possible role of Kv2.1 channel in metabolism to account for the perturbed metabolic traits we had reported [ 2 ]. However, in support of this possibility that Kv channels could be involved in body metabolic functions, Chandy and colleagues recently demonstrated that ShK-186, a selective and potent blocker of voltage-gated Kv1.3 channel, reduced weight gain, adiposity, and fatty liver with resultant enhancement of peripheral insulin sensitivity; and also decreased serum levels of cholesterol, glucose, HbA1c, insulin, and leptin [ 7 ].…”

Association of Single Nucleotide Polymorphisms in the Prostaglandin-endoperoxide Synthase 2 (PTGS2) and Phospholipase A2Group IIA (PLA2G2A) Genes with Susceptibility to Esophageal Squamous Cell Carcinoma

“…We used genotype data from the CHB panel (Han Chinese in Beijing) of the phase ⅡHapMap Project to select tag SNPs within the range of 5000bp upstream of the initiation codon and 5000bp downstream of the termination codon of the PLA2G2A gene on the basis of the following criteria: (1) r 2 linkage disequilibrium (LD) statistic >0.8 (Huang et al, 2009;Zhang et al, 2013); (2) minor allele frequency (MAF) >0.1; In addition to 13 tag SNPs in the PLA2G2A gene, 4 other tag SNPs (rs20417, rs689466, rs5275and rs12042763) in the PTGS2 gene were added to the set of markers, based on their functional relevance and significant association with cancer in previous studies (Zhang et al, 2005;Liu et al, 2006;Salinas et al, 2010;Liang et al, 2011;. Detailed information for all the tag SNPs including genomic position, genic position, minor allele frequency, and Hardy-Weinberg equilibrium are shown in Table 1.…”

Polygenic scores for major depressive disorder and depressive symptoms predict response to lithium in patients with bipolar disorder

“…Variants of the PREX1 gene on chromosome 20q12-13.1were associated with increased risk of diabetes mellitus type 2 and increased BMI in a cohort of European Americans 65 , through mechanisms are yet insufficiently understood 66 . Variants of the KCNB1 gene in humans are associated with increases of waist to hip ratio, fasting insulin, and triglycerides, as well as decreased insulin sensitivity 67,68 . Mechanistically, the KCNB1-encoded Kv2.1 and other K + v are important for the fine-tuning of the release of cellular insulin and other hormones or neurotransmitters, and have both inhibitory (through re-polarization of the membrane potential 69 ) and stimulating (through interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex) 70-73 effects on exocytotic mechanisms.…”