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.     

Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146

ObjectiveTCF7L2 variant rs7903146 is associated with increased risk for type 2 diabetes. We investigated the effect of TCF7L2 variant rs7903146 and glucose tolerance on free fatty acid (FFA) metabolism.Research Design and MethodsWe recruited 120 individuals, half homozygous for the major CC allele and half homozygous for the minor TT allele at rs7903146; each underwent a 2-h, 75 g oral glucose tolerance test (OGTT). Plasma glucose, insulin and free fatty acid concentrations were measured on blood collected before and during the OGTT.ResultsTotal FFA concentrations and percent FA species during OGTT were not different in CC and TT carriers when males and females were considered together. However, monounsaturated fatty acid (MUFA) concentrations and percentages were greater in TT than CC females during the OGTT. TT carriers with high HOMA-IR had significantly greater fasting FFA concentrations, lower disposition index (DI) and greater AUC of glucose than high HOMA-IR CC carriers, whereas no such differences were observed in the low HOMA-IR group. We found that fasting (826 ± 25 vs. 634 ± 22 μmol/L, P < 0.0001) and OGTT plasma FFA concentrations were greater in IGT than NGT subjects, and the difference remained after adjusting for sex, age, BMI, and genotype. Finally, IGT subjects had greater MUFA concentrations and percentages than NGT subjects during OGTT.ConclusionsDespite similar fasting insulin and glucose, fasting plasma FFA are greater in IGT than NGT adults. Insulin resistance and sex influence plasma FFA responses amongst carriers of the minor T allele of TCF7L2 rs7903146.     

<Emphasis Type="Italic">TCF7L2</Emphasis> single nucleotide polymorphisms,cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis We hypothesised that TCF7L2 single nucleotide polymorphisms (SNPs) are associated with cardiovascular disease (CVD) and that the associations differ in diabetic and non-diabetic persons. Methods Our analysis included black and white participants from the Atherosclerosis Risk in Communities study who were free of prevalent CVD at baseline and had been genotyped for rs7903146, rs12255372, rs7901695, rs11196205 and rs7895340 (n = 13,369). Cox proportional hazard regression was used to estimate the associations between polymorphisms and incident events; logistic and linear regression were used for associations with baseline risk factor levels. Results TCF7L2 SNPs were not significantly associated with incident coronary heart disease, ischaemic stroke, CVD, prevalent peripheral artery disease (PAD) or all-cause mortality in the full cohort or when stratified by race. Conclusions/interpretation In the whole cohort, TCF7L2 SNPs were not associated with incident CVD, all-cause mortality or prevalent PAD. This result suggests that the increased health risk associated with rs7903146 genotype is specific to diabetes.     

Association between plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipids with rs7903146 polymorphisms of the TCF7L2 gene in diabetic patients

The rs7903146 polymorphism of TCF7L2 gene is known as the strongest genetic risk factor for type 2 diabetes mellitus (T2DM). The polymorphism is in association with clinical profile of T2DM patients. PCSK9 is a serine protease that promotes LDLR degradation and regulates circulating levels of lipids. The association of this polymorphism with PCSK9 and metabolic profile of diabetic and healthy subjects was investigated. This cross-sectional study was performed on 132 T2DM patients and the same number of healthy subjects. All the participants were genotyped for the rs7903146 single nucleotide polymorphism by the PCR-RFLP method. Metabolic profile including plasma levels of PCSK9, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol, HDL cholesterol, fasting plasma glucose, and HBA1C was measured. PCSK9, total cholesterol, and LDL-C levels were lower in the diabetic patients as compared to the healthy subjects. There were also direct and significant associations between PCSK9 and TG, TC, LDL-C, and non HDL-C in the subjects. Values of plasma glucose, HbA1c, PCSK9, TC, and LDL-C were higher in patients with TT genotype, but the differences were not statistically significant for all. A positive Spearman correlation was found between PCSK9 levels and the genotypes in all the participants. The results confirm the association of rs7903146 in the TCF7L2 gene with metabolic parameters and PCSK9. The T allele was associated with higher lipid and PCSK9 levels.

     

Pleiotropic effects of TCF7L2 gene variants and its modulation in the metabolic syndrome: from the LIPGENE study

Aims/hypothesisVariants of the TCF7L2 gene predict the development of type 2 diabetes mellitus (T2DM). We investigated the associations between gene variants of TCF7L2 and clinical features of the metabolic syndrome (MetS) (an entity often preceeding T2DM), and their interaction with non-genetic factors, including plasma saturated fatty acids (SFA) concentration and insulin resistance (IR).MethodsFasting lipid profiles, insulin sensitivity, insulin secretion, anthropometrics, blood pressure and 10 gene variations of the TCF7L2 gene were determined in 450 subjects with MetS.ResultsSeveral single nucleotide polymorphisms (SNP) showed phenotypic associations independent of SFA or IR. Carriers of the rare T allele of rs7903146, and of three other SNPs in linkage disequilibrium with rs7903146, had lower blood pressure and insulin secretion. High IR and the presence of the T-allele of rs7903146 acted synergistically to define those with reduced insulin secretion. Carriers of the minor allele of rs290481 exhibited an altered lipid profile, with increased plasma levels of apolipoprotein B, non-esterified fatty acids, cholesterol and apolipoprotein B in triglyceride rich lipoproteins, and LDL cholesterol. Carriers of the minor allele of rs11196224 that had higher plasma SFA levels showed elevated procoagulant/proinflammatory biomarkers, impaired insulin secretion and increased IR, whereas carriers of the minor allele of rs17685538 with high plasma SFA levels exhibited higher blood pressure.Conclusions/interpretationSNP in the TCF7L2 gene are associated with differences in insulin secretion, blood pressure, blood lipids and coagulation in MetS patients, and may be modulated by SFA in plasma or IR.