KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta-analysis of 15,736 patients.
ABSTRACT: 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:KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus (T2DM) in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism (SNP) rs2237892 within KCNQ1 and TD2M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20-1.75). Genotypes CT (OR, 1.97; 95% CI, 1.24-3.15) and CC (OR, 2.49; 95% CI, 1.57-3.95) were associated with an increased risk of T2DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure (P=0.015), prevalence of hypertension (P=0.037), and risk of macrovascular disease (OR, 2.10; CI, 1.00-4.45) were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or TT. Therefore, our data support that KCNQ1 is associated with an increased risk for T2DM and might contribute to the higher incidence of hypertension and macrovascular complications in patients with T2DM carrying the risk allele C though it needs further to be confirmed in a larger population.
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: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:Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians.A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted.The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)).The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians.
Project description:<b>Background: </b>Type 2 diabetes mellitus (T2DM) is a multifactorial trait that both environmental and genetic factors contribute to its pathogenesis. The most common single nucleotide polymorphism (SNP) of the <i>potassium voltage-gated channel subfamily Q member 1 (KCNQ1)</i> gene, rs2237892, is highly associated with the risk of T2DM. The aim of the present study was to examine any association between <i>KCNQ1</i> gene rs2237892 variant and risk of T2DM in a group of Iranian patients.<br><br><b>Methods: </b>Genotyping was carried out in 100 type 2 diabetic patients and 100 non-diabetic subjects using the Sanger sequencing method.<br><br><b>Results: </b>The CC genotype caused more than 30% reduction in the risk of T2DM in compared with CT. Nonetheless, this association was not statistically significant and this variant had no protective effect for T2DM. A significant difference was not found in genotypes (CC, CT, and TT) and alleles (C and T) frequency of <i>KCNQ1</i> rs2237892 SNP between T2DM and control groups (<i>P</i>?=?0.475 and <i>P</i>?=?0.470, respectively).<br><br><b>Conclusions: </b>Our investigations did not show enough evidence for the presence of an association between <i>KCNQ1</i> gene rs2237892 polymorphism and risk of T2DM among a group of Iranian patients.
Project description:BACKGROUND: KCNQ1 (potassium voltage-gated channel KQT-like sub-family, member 1) encodes a pore-forming subunit of a voltage-gated K(+) channel (KvLQT1) that plays a key role for the repolarization of the cardiac action potential as well as water and salt transport in epithelial tissues. Recently, genome-wide association studies have identified KCNQ1 as a type 2 diabetes (T2D) susceptibility gene in populations of Asian descent. After that, a number of studies reported that the rs2237892 and rs2237895 polymorphism in KCNQ1 has been implicated in T2D risk. However, studies on the association between these polymorphism and T2D remain conflicting. To investigate this inconsistency, we performed this meta-analysis. METHODS: Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Potential sources of heterogeneity were also assessed by subgroup analysis and meta-regression. RESULTS: A total of 25 articles involving 70,577 T2D cases and 99,068 controls were included. Overall, the summary odds ratio of C allele for T2D was 1.32 (95% CI 1.26-1.38; P<10-5) and 1.24 (95% CI: 1.20-1.29; P<10-5) for KCNQ1 rs2237892 and rs2237895 polymorphisms, respectively. Significant results were also observed using co-dominant, dominant and recessive genetic models. After stratifying by ethnicity, sample size, and diagnostic criteria, significant associations were also obtained. CONCLUSIONS: This meta-analysis suggests that the rs2237892 and rs2237895 polymorphisms in KCNQ1 are associated with elevated type 2 diabetes susceptibility.
Project description:Several studies have investigated whether the polymorphism in the apolipoprotein A5 (APOA5) is associated with type 2 diabetes mellitus (T2DM) risk. However, those studies have produced inconsistent results. The purpose of this study was to investigate whether the APOA5 -1131T/C polymorphism (rs662799) confers significant susceptibility to T2DM using a meta-analysis.PubMed, Embase, Web of Science, Cochrane database, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0.A total of 19 studies included 4,767 T2DM cases and 10,370 controls (four studies involving 555 T2DM cases and 2958 controls were performed among Europeans and 15 studies involving 4212 T2DM cases and 7412 controls were performed among Asians) were combined showing significant association between the APOA5 -1131T/C polymorphism and T2DM risk (for C allele vs. T allele: OR?=?1.28, 95% CI?=?1.17-1.40, p<0.00001; for C/C vs. T/T: OR?=?1.57, 95% CI?=?1.35-1.83, p<0.00001; for C/C vs. T/C+T/T: OR?=?1.36, 95% CI?=?1.18-1.57, p<0.0001; for C/C+T/C vs. T/T: OR?=?1.32, 95% CI?=?1.16-1.51, p<0.0001). In the subgroup analysis by ethnicity, significant association was also found among Asians (for C allele vs. T allele: OR?=?1.31, 95% CI?=?1.22-1.40, p<0.00001; for C/C vs. T/T: OR?=?1.61, 95% CI?=?1.38-1.88, p<0.00001; for C/C vs. T/C+T/T: OR?=?1.39, 95% CI?=?1.20-1.61, p<0.0001; for C/C+T/C vs. T/T: OR?=?1.42, 95% CI?=?1.25-1.62, p<0.00001). However, no significant association was found between the APOA5 -1131T/C polymorphism and T2DM risk among Europeans.The present meta-analysis suggests that the APOA5 -1131T/C polymorphism is associated with an increased T2DM risk in Asian 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:OBJECTIVE: The potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) has been found through a genome-wide association study to be a strong candidate for conferring susceptibility to type 2 diabetes in East Asian and European populations. Our objective was to describe the association between polymorphisms at the KCNQ1 locus with insulin resistance, beta-cell function, and other type 2 diabetes-related traits in a sample of Chinese, Malays, and Asian Indians living in Singapore. RESEARCH DESIGN AND METHODS: We examined the associations between four previously reported KCNQ1 single-nucleotide polymorphisms (SNPs) with type 2 diabetes-related traits in 3,734 participants from the population-based 1998 Singapore National Health Survey cohort (2,520 Chinese, 693 Malay, and 521 Asian Indians). Insulin resistance was calculated from fasting insulin and glucose using the homeostasis model assessment method, whereas pancreatic beta-cell function was assessed using the corrected insulin response at 120 min (CIR(120)). RESULTS: SNPs rs2237897, rs2237892, and rs2283228 were significantly associated with type 2 diabetes (odds ratio [OR] 1.48, P = 3 x 10(-4); OR 1.38, P = 0.002; OR 1.31, P = 0.012, respectively). Within the Chinese population, the risk alleles for rs2237897, rs2237892, and rs2283228 were significantly associated with higher fasting glucose levels (P = 0.014, 0.011, and 0.034, respectively) and reduced CIR(120)(P = 0.007, 0.013, and 0.014, respectively). A similar trend was observed among the Malay and Asian Indian minority groups, although this did not reach statistical significance because of limited sample sizes. CONCLUSIONS: The increased risk for type 2 diabetes associated with KCNQ1 is likely to be caused by a reduction in insulin secretion. Further studies will be useful to replicate these findings and to fully delineate the role of KCNQ1 and its related pathways in disease pathogenesis.