Transcription factor 7-like 2 (TCF7L2) gene polymorphism rs7903146 is associated with stroke in type 2 diabetes patients with long disease duration

Associations between TCF7L2 SNP and diabetic complications and diabetes-related factors were investigated. Subjects with rs7903146 variant had significantly higher prevalence of stroke (24.1% vs. 11.1%; P = 0.039) among subjects exhibiting a long disease duration (≥10 years). In conclusion, the TCF7L2 SNP variant may confer a higher risk of stroke in diabetic patients.     

TCF7L2基因与2型糖尿病

转录因子7类似物2(TCF7L2)常见变异在不同的种族中几乎都与2型糖尿病显著相关.TCF7L2剪接有显著的组织特异性,在2型糖尿病患者的胰岛内TCF7L2 mRNA水平增高.其变异与胰岛素分泌功能减退有关,机制可能是其特异性损害肠促胰素(incretin)如胰高血糖素样肽-1(GLP-1)诱导的胰岛素分泌,也可能因胰岛素原向胰岛素的转换异常,和(或)参与Wnt信号通路的激活而致2型糖尿病.因此对2型糖尿病致病基因TCF7L2基因的研究有助于揭示糖尿病的发病机制、病理生理及为糖尿病的治疗提供新的靶点.     

TCF7L2 rs7903146 polymorphism is associated with gastric cancer: a case-control study in the Venezuelan population

AIM: To explore the association between TCF7L2 rs12255372 and rs7903146 single nucleotide polymorphisms(SNPs) and gastric cancer risk in Venezuelan patients.METHODS: We performed a case-control study including 122 paraffin-embedded archived intestinaltype gastric cancer samples and 129 biopsies obtained by superior endoscopy from chronic gastritis patients. Gastric cancer samples were classified according the degree of carcinoma differentiation. Genomic DNA was extracted from tissues, and the two SNPs of TCF7L2 gene(rs12255372 and rs7903146) were genotyped by polymerase chain reaction-restriction fragment length polymorphism reactions. Multiple regression analysis with adjustments for age and gender were performed and best-fitting models of inheritance were determined.RESULTS: After adjusting for age and sex the TCF7L2 rs7903146 TT genotype was associated with gastric cancer risk under the recessive genetic model(OR = 3.11, 95%CI: 1.22-7.92, P = 0.017). We further investigated the distribution of rs12255372 and rs7903146 genotypes according gastric cancer stratified by degree of differentiation, and we observed that carriers of rs7903146 T allele(CT + TT vs CC) had a significantly increased risk of moderate/well differentiated gastric cancer(dominant model, OR = 2.55, 95%CI: 1.35-4.80, P = 0.004), whereas the rs7903146 TT genotype was associated with poorly differentiated gastric cancer in the recessive model(OR = 3.65, 95%CI: 1.25-10.62, P = 0.018). We did not find association between rs12255372 SNP and the susceptibility of developing gastric cancer. CONCLUSION: TCF7L2 rs7903146 polymorphism is associated with gastric cancer risk in the Venezuelan population, and could be related to determine the degree of differentiation of tumor cells.     

TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study

Aims/hypothesis  Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS). Methods  We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures. Results  As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 × 10⁻⁷) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92). Conclusions/interpretation  We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

转录因子7类似物2基因rs11196205多态性与安徽地区2型糖尿病及糖调节受损的相关性

目的 探讨转录因子7类似物2(TCF7L2)基因rs11196205位点多态性在安徽地区汉族人群中与2型糖尿病(T2DM)和糖调节受损(IGR)的相关性.方法 选取2009年1月至8月于安徽医科大学第一附属医院就诊的2型糖尿病患者300例、糖调节受损患者300例和糖耐量正常对照者(NGT)300名,收集临床资料和采集血样,测定生化指标并提取DNA;探针固定于芯片,PCR制备荧光标记靶基因与芯片杂交,扫描杂交结果;采用单因素方差分析及K-W检验统计分析rs11196205突变等位基因和基因型频率与T2DM及IGR发病的关系.结果 TCF7L2基因rs11196205位点等位基因频率[C在T2DM、IGR、NGT组频率分别为21%(126/600)、19%(114/600)、11%(68/600)]和基因型频率[GC+CC在T2DM、IGR、NGT组频率分别为41%(122/300)、37%(111/300)、22%(67/300)].T2DM与NGT、IGR与NGT、T2DM+IGR与NGT 3组比较差异均有统计学意义(P<0.05).携带突变等位基因C可增加罹患T2DM(OR=2.08,95%C1=1.51～2.86,X2=20.68,P<0.05)、IGR(OR=1.84,95%CI=1.33～2.54,X2=13.71,P<0.05)或任何一种(OR=1.96,95%CI=1.46～2.61,X2=21.18,P<0.05)的风险.与野生纯合基因型GG比较,体内携带一个以上突变基因C复本可增加罹患T2DM(OR:2.38,95%CI=1.67～3.40,X2=23.37,P<0.05)、IGR(OR=2.04,95%CI=1.43～2.92,X2=15.46,P<0.05)或任何一种(OR=2.21,95%CI=1.61～3.03,X2=24.50,P<0.05)的风险.结论 rs11196205位点G→C突变在安徽地区汉族人群中可能与T2DM和IGR关联,携带突变等位基因C可显著增加罹患T2DM和IGR的风险.     

TCF7L2 gene expression in human visceral and subcutaneous adipose tissue is differentially regulated but not associated with type 2 diabetes mellitus

Variants in the TCF7L2 gene have been associated with type 2 diabetes mellitus (T2DM), but the causal variant(s) is still unknown. We studied the TCF7L2 messenger RNA (mRNA) expression in paired samples of visceral and subcutaneous adipose tissue from 49 subjects using quantitative real-time polymerase chain reaction and its relation to obesity and T2DM. All subjects were genotyped for the previously described TCF7L2 diabetes risk variants. Independent of age, sex, obesity, and diabetes status, we found >3-fold higher TCF7L2 mRNA expression in subcutaneous compared with visceral adipose tissue. There was no correlation between visceral and subcutaneous TCF7L2 expression. No differences in adipose tissue TCF7L2 mRNA expression levels were found between diabetic and nondiabetic subjects, or between lean and obese subjects (all Ps > .05). In addition, there was no association between TCF7L2 genetic variants and mRNA expression. Based on our data, TCF7L2 mRNA expression is fat-depot specific but does not seem to provide the mechanistic link explaining genetic association with T2DM.