Association of Genetic Variants of KCNJ11 and KCNQ1 Genes with Risk of Type 2 Diabetes Mellitus (T2DM) in the Indian Population: A Case-Control Study.
ABSTRACT: Type 2 diabetes mellitus (T2DM) is a polygenic metabolic disease described by hyperglycemia, which is caused by insulin resistance or reduced insulin secretion. The interaction between various genetic variants and environmental factors triggers T2DM. The aim of this study was to find risk associated with genetic variants rs5210 and rs2237895 of KCNJ11 and KCNQ1 genes, respectively, in the development of T2DM in the Indian population. A total number of 300 cases of T2DM and 100 control samples were studied to find the polymorphism in KCNJ11 and KCNQ1 through PCR-RFLP. The genotype and allele frequencies in T2DM cases were significantly different compared to the control population. KCNJ11 rs5210 and KCNQ1 rs2237895 variants were found to be significantly associated with risk of T2DM in dominant (KCNJ11: OR, 2.07; 95% CI, 1.30-3.27; p - 0.001; KCNQ1: OR, 2.33; 95% CI, 1.46-3.70; p - 0.0003) and codominant models (KCNJ11: OR, 1.76; 95% CI, 1.09-2.84; p - 0.020; KCNQ1: OR, 1.85; 95% CI, 1.16-2.95; p - 0.009). We also compared clinicopathological characteristics between cases and control and observed a significant difference in all the parameters except HDL, gender, and family history. In this study, clinicopathological data with a carrier of a variant allele of both KCNJ11 and KCNQ1 genes were also analysed, and a significant association was found between the carrier of a variant allele with gender and PPG in KCNJ11 and with triglyceride in KCNQ1. We confirm the significant association of KCNJ11 (rs5210) and KCNQ1 (rs2237895) gene polymorphism with T2DM, indicating the role of these variants in developing risk for T2DM in Indian population.
Project description:Background: Type 2 diabetes mellitus (T2DM) has a high global prevalence, and insufficient insulin secretion is one of the major reasons for its development. Therefore, investigating the association between T2DM and the single nucleotide polymorphisms (SNPs) in genes associated with insulin secretion is necessary. Methods: T2DM (1,194) and nondiabetic (NDM) (1,292) subjects were enrolled and the ten single nucleotide polymorphisms (SNPs) in KCNQ1, ARAP1, and KCNJ11 associated with insulin secretion were genotyped in a Chinese population. Results: Our data revealed that the rs2237897T allele in KCNQ1 is the protective allele for T2DM (P<0.001, OR=0.793; 95%CI: 0.705-0.893). However, the A allele of rs1552224 in ARAP1 may be a risk factor for T2DM (P=0.002, OR=12.070; 95% CI: 1.578-92.337). The haplotype analysis revealed that rs151290-rs2237892CC and rs2237895-rs2237897CC in KCNQ1 constitute the risk haplotype in T2DM development (P=0.010, OR=1.160; 95% CI: 1.037-1.299 and P=0.004, OR=1.192; 95% CI: 1.057-1.344). Moreover, rs2237895-rs2237897AT in KCNQ1 constitutes the protective haplotype in T2DM (P=0.001, OR=0.819; 95% CI: 0.727-0.923). In the inheritance models analysis, the rs2283228 (C/A-C/C) genotype is the protective factor compared to the A/A genotype (P=0.005, OR=0.79; 95% CI: 0.68-0.93). For rs2237897, the C/T-T/T genotype is the protective factor compared to the C/C genotype (P<0.001, OR=0.74; 95% CI: 0.63-0.87). Furthermore, when compared with the rs2237897 (C/T-T/T) genotype, rs2237897C/C genotype showed higher HbA1C levels (8.731±2.697 vs 9.282±2.921, P=0.001). Conclusion: Our results revealed that genetic variations in KCNQ1 and ARAP1 were associated with T2DM susceptibility in a Chinese population.
Project description:Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through ? cell function.
Project description:Type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) share a common pathophysiology. However, diabetes mellitus is a complex disease, and T2DM and PTDM have different etiologies. T2DM is a metabolic disorder, characterized by persistent hyperglycemia, whereas PTDM is a condition of abnormal glucose tolerance, with variable onset after organ transplant. The KCNQ1 and KCNJ11 gene encode potassium channels, which mediate insulin secretion from pancreatic ?-cells, and KCN gene mutations are correlated with the development of diabetes. However, no studies have been carried out to establish an association between KCNQ1 and KCNJ11 gene polymorphisms and T2DM and PTDM. Therefore, our study was aimed at the identification of the role of KCNQ1 and KCNJ11 gene polymorphisms associated with T2DM and the risk of developing PTDM in the Asian Indian population. We have carried out a case-control study including 250 patients with T2DM, 250 control subjects, 42 patients with PTDM and 98 subjects with non-PTDM. PCR-RFLP analysis was carried out following the isolation of genomic DNA from EDTA-blood samples. The results of the present study reveal that two single nucleotide polymorphisms (rs2283228 and rs5210, of the KCNQ1 and KCNJ11 genes, respectively) are associated with both T2DM and PTDM. The results of our study suggest a role of KCNQ1 and KCNJ11 gene variants in the increased risk of T2DM and PTDM in the Asian Indian population.
Project description:KCNQ1 channel is a member of the voltage-gated potassium channel KQT-like subfamily. The KCNQ1 gene has recently been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). In the present study, we examined the effects of KCNQ1 variants on the therapeutic response to modified-release gliclazide (gliclazide MR) treatment in Chinese patients newly diagnosed with T2DM. A total of 100 newly diagnosed T2DM patients without a history of any anti-diabetic medications were treated with gliclazide MR for 16 weeks, but 91 patients completed the entire study. The anthropometric parameters were determined at baseline and at the final visit, while clinical laboratory tests were performed at baseline and on weeks 2, 4, 6, 12, 16. Two SNPs, rs2237892 and rs2237895, in the region of the KCNQ1 gene were genotyped in all the participants. All calculations and statistical analyses were conducted using SPSS. The rs2237892 TT homozygotes exhibited significantly higher 2-h glucose levels at baseline (P<0.05) and a lower cumulative attainment rate of the target 2-h glucose level (Plog-rank=0.020) than the C allele carriers. Patients with greater numbers of rs2237892 T alleles exhibited larger augmentations (Δ) in the 2-h glucose levels (P=0.027); and patients with the rs2237892 TT genotype exhibited a higher Δ homeostasis model assessment of β-cell function (HOMA-β) than CC and CT genotype carriers (P=0.021 and P=0.043, respectively). Moreover, the rs2237895 C allele was associated with a greater decrement in Δ glycated hemoglobin (HbA1c) (P=0.024); and patients with the CC genotype exhibited greater variance than those with the AA and AC genotypes (P=0.005 and 0.021, respectively). Compared with the C allele, the odds ratio for treatment success among carriers of the rs2237892 T allele was 2.533 (P=0.007); and the rs2237895 C allele was associated with a 2.360-fold decrease in HbA1c compared with the A allele (P=0.009). KCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.
Project description:The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta-analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random-effect or fixed-effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240-1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570-0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286-1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275-1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.
Project description:Genetic variants at KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963 have been associated with type 2 diabetes mellitus (T2DM), but the results are contradictory in Chinese populations. The aim of the present study was to investigate the association of these four SNPs with T2DM in a large population of Han Chinese at Henan province, China. Seven-hundred-thirty-six patients with T2DM (cases) and Seven-hundred-sixty-eight healthy glucose-tolerant controls were genotyped for KCNQ1 rs151290, KLF14 rs972283, GCKR rs780094 and MTNR1B rs10830963. The association of genetic variants in these four genes with T2DM was analyzed using multivariate logistic regression. Genotypes and allele distributions of KCNQ1 rs151290 were significantly different between the cases and controls (p < 0.05). The AC and CC genotypes and the combined AC + CC genotype of rs151290 in KCNQ1 were associated with increases risk of T2DM before (OR = 1.482, 95% CI = 1.062-2.069; p = 0.021; OR = 1.544, 95% CI = 1.097-2.172, p = 0.013; and OR = 1.509, 95% CI = 1.097-2.077, p = 0.011, respectively) and after (OR = 1.539, 95% CI = 1.015-2.332, p = 0.042; OR = 1.641, 95% CI = 1.070-2.516, p = 0.023; and OR = 1.582, 95% CI = 1.061-2.358, p = 0.024; respectively) adjustment for sex, age, anthropometric measurements, biochemical indexes, smoking and alcohol consumption. Consistent with results of genotype analysis, the C allele of rs151290 in KCNQ1 was also associated with increased risk of T2DM (OR = 1.166, 95% CI = 1.004-1.355, p = 0.045). No associations between genetic variants of KLF14 rs972283, GCKR rs780094 or MTNR1B rs10830963 and T2DM were detected. The AC and CC genotypes and the C allele of rs151290 in KCNQ1 may be risk factors for T2DM in Han Chinese in Henan province.
Project description:Background:Previous studies have examined the role of the KQT-like subfamily Q member1 (KCNQ1) gene polymorphisms on the risk of type 2 diabetes mellitus (T2DM), but the findings are inconclusive. Objective:To examine the association between the KCNQ1 gene polymorphisms and the risk of T2DM using an updated meta-analysis with an almost tripled number of studies. Methods:Five electronic databases, such as PubMed and Embase, were searched thoroughly for relevant studies on the associations between seven most studied KCNQ1 gene polymorphisms, including rs2237892, rs2237897, rs2237895, rs2283228, rs231362, rs151290, and rs2074196, and T2DM risk up to September 14, 2019. The summary odds ratios (ORs) with their 95% confidence intervals (CIs) were applied to assess the strength of associations in the random-effects models. We used the trial sequential analysis (TSA) to measure the robustness of the evidence. Results:49 publications including 55 case-control studies (68,378 cases and 66,673 controls) were finally enrolled. In overall analyses, generally, increased T2DM risk was detected for rs2237892, rs2237895, rs2283228, rs151290, and rs2074196, but not for rs231362 under all genetic models. The ORs and 95% CIs for allelic comparison were 1.23 (1.14-1.33) for rs2237892, 1.21 (1.16-1.27) for rs2237895, 1.27 (1.11-1.46) for rs2237897, 1.25 (1.09-1.42) for rs2283228, 1.14 (1.03-1.27) for rs151290, 1.31 (1.23-1.39) for rs2074196, and 1.16 (0.83, 1.61) for rs231362. Stratified analyses showed that associations for rs2237892, rs2237895, rs2283228, and rs151290 were more evident among Asians than Caucasians. TSA demonstrated that the evidence was sufficient for all polymorphisms in this study. The genotypes of the three SNPs (rs2237892, rs2283228, and rs231362) were significantly correlated with altered KCNQ1 gene expression. Conclusion:This meta-analysis suggested that KCNQ1 gene polymorphisms (rs2237892, rs2283228, rs2237895, rs151290, and rs2074196) might be the susceptible factors for T2DM, especially among Asian population.
Project description:To examine whether diabetes-related genetic variants are associated with pancreatic cancer risk.We genotyped 7 single-nucleotide polymorphisms (SNPs) in PPARG2 (rs1801282), ADIPOQ (rs1501299), ADRB3 (rs4994), KCNQ1 (rs2237895), KCNJ11 (rs5219), TCF7L2 (rs7903146), and CDKAL1 (rs2206734), and examined their associations with pancreatic cancer risk in a multi-institute case-control study including 360 cases and 400 controls in Japan. A self-administered questionnaire was used to collect detailed information on lifestyle factors. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these diabetes-associated variants and pancreatic cancer risk.With the exception of rs1501299 in the ADIPOQ gene (P = 0.09), no apparent differences in genotype frequencies were observed between cases and controls. Rs1501299 in the ADPIOQ gene was positively associated with pancreatic cancer risk; compared with individuals with the AA genotype, the age- and sex-adjusted OR was 1.79 (95%CI: 0.98-3.25) among those with the AC genotype and 1.86 (95%CI: 1.03-3.38) among those with the CC genotype. The ORs remained similar after additional adjustment for body mass index and cigarette smoking. In contrast, rs2237895 in the KCNQ1 gene was inversely related to pancreatic cancer risk, with a multivariable-adjusted OR of 0.62 (0.37-1.04) among individuals with the CC genotype compared with the AA genotype. No significant associations were noted for other 5 SNPs.Our case-control study indicates that rs1501299 in the ADIPOQ gene may be associated with pancreatic cancer risk. These findings should be replicated in additional studies.
Project description:Objective:The genetic variant rs2237895, located in the Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1) gene, has been replicated to be associated with type 2 diabetes mellitus (T2DM) susceptibility, but the relationship with lipids is conflicting. Furthermore, the common genetic predisposition to T2DM and lipids was not fully detected. Methods:In total, 5839 individuals (2220 were T2DM patients) across 2885 families were included. The effect of rs2237895 on T2DM and lipids was estimated using linear regression and logistic regression models after adjustment for multiple covariates. Mediation analysis was then used to test whether KCNQ1 participated in T2DM pathogenesis via lipid-mediated pathways. Results:Per allele-C of rs2237895 was associated with 17% (11-23%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%, P < 0.001) increased T2DM risk. Moreover, it was correlated with 5% (1-9%. Conclusion:KCNQ1 had pleiotropic effects on lipids and T2DM, and the unexpected genetic effect on association of HDL-C with T2DM was observed, indicating the different pathways to lipids and T2DM. Further research studies are needed to verify potential biological mechanisms.
Project description: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.