Common Variants in KCNQ1 Confer Increased Risk of Type 2 Diabetes and Contribute to the Diabetic Epidemic in East Asians: A Replication and Meta-Analysis

Wang, Haoran; Miao, Kun; Zhao, Jinzhao; Liu, Lei; Cui, Guanglin; Chen, Chen; Wang, Dao Wen; Ding, Hu

doi:10.1111/ahg.12029

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…The sensitivity analysis indicated that most of our results in all genetic models for the 7 included polymorphisms were robust after excluding any single study, except for the results for the heterozygote comparison of rs2237897, the allelic comparison and recessive genetic model of rs231362, and the allelic comparison and recessive genetic model of rs151290, after excluding the study by Wang et al [17], Ohshige et al [59], and Yasuda et al [48], respectively.…”

Section: Sensitivity Analysismentioning

confidence: 73%

Associations ofKCNQ1Polymorphisms with the Risk of Type 2 Diabetes Mellitus: An Updated Meta-Analysis with Trial Sequential Analysis

Liao

Zeng³

et al. 2020

Journal of Diabetes Research

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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.

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Section: Sensitivity Analysismentioning

confidence: 73%

Associations ofKCNQ1Polymorphisms with the Risk of Type 2 Diabetes Mellitus: An Updated Meta-Analysis with Trial Sequential Analysis

Liao

Zeng³

et al. 2020

Journal of Diabetes Research

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“…9 The significant associations between risk alleles for rs2237892, rs2237895, rs2283228, and rs231362 of KCNQ1 and T2DM risk were consistent in our study and meta-analyses. 10,11,33 However, a metaanalysis in an east Asian population 10 and a nested casecontrol study in Japan 34 identified a significant association between rs2237892 of KCNQ1 and T2DM risk in a recessive and dominant model. The association between rs2237892 of KCNQ1 and T2DM risk may be affected by unmeasured confounding factors and rare risk alleles in a population.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of probability of type 2 diabetes mellitus with polymorphisms and methylation of KCNQ1 gene: A nested case‐control study

Zhang

Qin

et al. 2021

Journal of Diabetes

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Background: To estimate the associations between single-nucleotide polymorphisms (SNPs) and methylation of KCNQ1 gene and type 2 diabetes mellitus (T2DM) risk and the interactions among SNPs, methylation, and environmental factors on T2DM risk. Methods:We genotyped five SNPs and tested methylation at 39 CpG loci of KCNQ1 in 290 T2DM cases and 290 matched controls nested in the Rural Chinese Cohort Study. Conditional logistic regression model was used to estimate the associations between SNPs and KCNQ1 methylation and T2DM risk. Multifactor dimensionality reduction (MDR) analysis was used to estimate the effect of the interactions SNPs-SNPs, SNPs-methylation, methylation-methylation and SNPs, and methylation-environment on T2DM risk.Results: Probability of T2DM was decreased with rs2283228 of KCNQ1 (CA vs AA, odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.42-0.99). T2DM probability was significantly increased with rs2237895 combined with hypertriglyceridemia (OR eg = 2.76, 95% CI 1.35-5.62), with hypertension (OR eg = 2.23, 95% CI 1.25-3.98), and with body mass index (BMI; OR eg = 1.93, 95% CI 1.12-3.34). T2DM probability was associated with methylation of CG11 and CG41 (OR = 1.89, 95% CI 1.23-2.89, P = .003). It was significantly associated with the interaction between BMI, hypertriglyceridemia, and CG5 methylation (P = .028 and .028), and the combined effects of CG11 with hypertriglyceridemia and hypertension. On MDR analysis, no significant interaction was observed.Conclusion: T2DM probability was reduced 35% with rs2283228 polymorphism. It was associated with rs2237895 combined with hypertension, with BMI and with hypertriglyceridemia. The methylation at two CpG loci of KCNQ1 significantly increased T2DM risk by 89%.

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“…Genetic variations in the sequence of KCNQ1 such as rs2237892 cause changes in the translation and/or in post-translational modifications, reducing β cells function ( Jonsson et al, 2009 ). Thus, a decreased secretory capacity of the β cells could increase GDM risk by reducing the secretory capacity of insulin and limiting its compensation ( Wang et al, 2013 ). In fact, GDM patients carrying the risk allele have higher fasting plasma glucose levels and lower insulin secretion ( Wang et al, 2013 ).…”

Section: Genetic Factors Associated With Gestational Diabetes Mellitu...mentioning

confidence: 99%

“…Thus, a decreased secretory capacity of the β cells could increase GDM risk by reducing the secretory capacity of insulin and limiting its compensation ( Wang et al, 2013 ). In fact, GDM patients carrying the risk allele have higher fasting plasma glucose levels and lower insulin secretion ( Wang et al, 2013 ).…”

Section: Genetic Factors Associated With Gestational Diabetes Mellitu...mentioning

confidence: 99%

Pathophysiological Role of Genetic Factors Associated With Gestational Diabetes Mellitus

et al. 2022

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Gestational Diabetes Mellitus (GDM) is a highly prevalent maternal pathology characterized by maternal glucose intolerance during pregnancy that is, associated with severe complications for both mother and offspring. Several risk factors have been related to GDM; one of the most important among them is genetic predisposition. Numerous single nucleotide polymorphisms (SNPs) in genes that act at different levels on various tissues, could cause changes in the expression levels and activity of proteins, which result in glucose and insulin metabolism dysfunction. In this review, we describe various SNPs; which according to literature, increase the risk of developing GDM. These SNPs include: (1) those associated with transcription factors that regulate insulin production and excretion, such as rs7903146 (TCF7L2) and rs5015480 (HHEX); (2) others that cause a decrease in protective hormones against insulin resistance such as rs2241766 (ADIPOQ) and rs6257 (SHBG); (3) SNPs that cause modifications in membrane proteins, generating dysfunction in insulin signaling or cell transport in the case of rs5443 (GNB3) and rs2237892 (KCNQ1); (4) those associated with enzymes such as rs225014 (DIO2) and rs9939609 (FTO) which cause an impaired metabolism, resulting in an insulin resistance state; and (5) other polymorphisms, those are associated with growth factors such as rs2146323 (VEGFA) and rs755622 (MIF) which could cause changes in the expression levels of these proteins, producing endothelial dysfunction and an increase of pro-inflammatory cytokines, characteristic on GDM. While the pathophysiological mechanism is unclear, this review describes various potential effects of these polymorphisms on the predisposition to develop GDM.

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Common Variants in KCNQ1 Confer Increased Risk of Type 2 Diabetes and Contribute to the Diabetic Epidemic in East Asians: A Replication and Meta-Analysis

Cited by 11 publications

References 43 publications

Associations ofKCNQ1Polymorphisms with the Risk of Type 2 Diabetes Mellitus: An Updated Meta-Analysis with Trial Sequential Analysis

Associations ofKCNQ1Polymorphisms with the Risk of Type 2 Diabetes Mellitus: An Updated Meta-Analysis with Trial Sequential Analysis

Integrated analysis of probability of type 2 diabetes mellitus with polymorphisms and methylation of KCNQ1 gene: A nested case‐control study

Pathophysiological Role of Genetic Factors Associated With Gestational Diabetes Mellitus

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