Type 2 diabetes associated variants of KCNQ1 strongly confer the risk of cardiovascular disease among the Saudi Arabian population

Abstract

Genome-wide association studies have identified several loci associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes (T2D). Polymorphisms within the KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene are consistently associated with T2D in a number of populations. The current study was undertaken to evaluate the association of 3 polymorphisms of KCNQ1 (rs2237892, rs151290 and rs2237895) with T2D and/or CVD. Patients diagnosed with either T2D (320 patients), CVD (250 patients) or both (60 patients) and 516 healthy controls were genotyped by TaqMan assay run on a real time PCR thermocycler. A statistically significant association was found for SNPs rs151290 (OR = 1.76; 95%CI = 1.02-3.05; p = 0.0435) and rs2237895 (OR = 2.49; 95%CI = 1.72-3.61; p < 0.0001) with CVD. SNP rs151290 (OR = 7.43; 95%CI = 1.00-55.22; p = 0.0499) showed a strong association in patients with both T2D and CVD. None of the SNPs showed any significant association with T2D. Haploview analysis showed that the ACC (rs151290, rs2237892 and rs2237895) haplotype is the most significant risk allele combination for CVD, while CCA is the most significant risk haplotype for co-morbidity with T2D. KCNQ1 polymorphism at SNPs rs151290 and rs2237895 is strongly associated with CVD in this population, but presented no association with T2D.

Single-nucleotide polymorphisms in a cohort of significantly obese women without cardiometabolic diseases

“…Additionally, we identified an intron variant of the Potassium Voltage-Gated Channel Subfamily Q Member 1 gene ( KCNQ1 ) that associated with the MHO phenotype (p=1×10 −5 ). Several studies have reported KCNQ1 polymorphism associations for obesity, type 2 diabetes, or cardiovascular risk 25, 26 .…”

Association of Combined TCF7L2 and KCNQ1 Gene Polymorphisms with Diabetic Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus

“…The genetic susceptibility to T2DM has been widely investigated. Several single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2), the potassium voltage-gated channel subfamily Q member 1 gene (KCNQ1), and the inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) have reported to be associated with the development of T2DM and its vascular complications [7][8][9][10][11][12][13][14][15][16][17][18], with variable results among the different ethnic population. TCF7L2 is the transcriptional effector in the canonical Wnt-signaling pathway involving in the regulation of incretin hormone production, pancreatic β-cell development, vascular development, and may involve in insulin signaling [19,20].…”

“…Although the association of polymorphisms in TCF7L2, KCNQ1, and KCNJ11 genes with T2DM have consistently replicated in multiple ethnic groups, their association with vascular complications remains inconsistent [7][8][9][10][11][12][13][14][15][16][17][18]. The influence of single SNPs on the risk of diabetic complications generally has a modest effect, therefore the cumulative effect of multiple risk alleles as genetic risk score (GRS) may provide a better tool for the evaluation of the risk for T2DM-related complications.…”

Molecular determinants of the modulation of the VSD-PD coupling mechanism of the KV7.1 channel by the KCNE1 ancillary subunits

“…Several studies also reported the existence of single nucleotide polymorphisms (SNPs) in the KCNQ1 gene that are associated with the appearance of type 2 diabetes (Adeyemo et al, 2015;Al-Shammari et al, 2017;Li et al, 2017;Mussig et al, 2009). Hence, IKS channel constitute a major therapeutic target for the treatment of these channelopathies (Kim, 2014).…”