Association of TCF7L2 rs7903146 Gene Polymorphism with the Risk of NAFLD and CAD in the Chinese Han Population.
ABSTRACT: Background and Aims: Coronary artery disease (CAD) is a major cause of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that TCF7L2 rs7903146 was related to the risk of developing NAFLD but the conclusions are not consistent and no related study has been conducted in Chinese populations. The aim of this study was to investigate the association between TCF7L2 rs7903146 and the risk of developing NAFLD and CAD in a Chinese Han population. Methods:TCF7L2 rs7903146 genotypes were measured by the MALDI-TOF-MS from 143 NAFLD patients, 159 CAD patients, 131 NAFLD + CAD patients, and 212 healthy controls. The demographic data and serum lipid profiles of all subjects were collected. The distributions of genotype and allele frequency in each group were also tested. Logistic regression was used to investigate the risk of TCF7L2 rs7903146 with NAFLD and CAD. All statistical analyses were conducted using SPSS 23.0. Results: There were no significant differences in the distributions of TCF7L2 rs7903146 genotype and allele frequency in each of the two groups, and the TCF7L2 rs7903146 CT + TT genotype did not increase the risk of developing NAFLD, CAD, and NAFLD + CAD. Except for body mass index in the control group, the differences of clinical parameters between the TCF7L2 rs7903146 T allele carriers and non-carriers in each group were not significant. In the non-obese group, the TCF7L2 rs7903146 CT + TT genotype was a protective factor for the development of NAFLD in the non-obese subjects (odds ratio=0.359, 95% confidence interval: 0.134-0.961, p = 0.041). Conclusions:TCF7L2 rs7903146 was not associated with the risk of developing NAFLD, CAD, and NAFLD + CAD in the Chinese Han population. In the non-obese population, the TCF7L2 rs7903146 CT + TT genotype was a protective factor against the development of NAFLD.
Project description:To explore the association between TCF7L2 rs12255372 and rs7903146 single nucleotide polymorphisms (SNPs) and gastric cancer risk in Venezuelan patients.We performed a case-control study including 122 paraffin-embedded archived intestinal-type 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. Statistic powers were post-hoc calculated.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.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.
Project description:Background:The TCF7L2 rs7903146 variant is strongly associated with type 2 diabetes mellitus (T2DM). However, the mechanisms involved in this association remain unknown and may include extrapancreatic effects. The aim of this study was to perform a metabolic characterization of T2DM patients with and without the TCF7L2 rs7903146 risk T allele and analyze some influences of the TCF7L2 genotype on glucose metabolism. Methods:Patients with T2DM (n?=?162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism. Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C, HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon. Additional secondary assessments included determination of insulinogenic index (IGI30), and insulin sensitivity (%S) and resistance (IR) by Homeostatic model assessment (HOMA). Results:Patients with the CT/TT genotype showed lower baseline plasma concentrations of C-peptide when compared with those with the CC genotype. Of the 56 individuals who participated in the mixed-meal test, 26 and 30 had the CC and CT/TT genotypes, respectively. CT/TT subjects, compared with CC individuals, had higher post prandial plasma levels of insulin and C-peptide at 30-120 min (p?<?0.05) and proinsulin at 45-240 min (p?<?0.05). Interestingly CT/TT individuals presented at baseline higher %S (p?=?0.021), and lower IR (p?=?0.020) than CC individuals. No significant differences in IGI30 values were observed between groups. Conclusions:The T2DM individuals carrying the rs7903146 T allele of the TCF7L2 gene presented higher IR pattern in response to a mix-meal test, different of beta cell function at baseline assessed by C-peptide levels which was lower, and Homa-IR was lower when comparing with non-carriers.
Project description:OBJECTIVE:This study aimed at investigating the association between the rs7903146 (C/T) polymorphism of the TCF7L2 gene with obesity in a Cameroonian population. METHOD:This was a case-control pilot study including 61 obese and 61 non-obese Cameroonian adults. Anthropometric indices of obesity, blood pressure, fasting blood glucose, and blood lipids were measured. The rs7903146 (C/T) polymorphism of the TCF7L2 gene was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and genotypes were correlated with clinical and biological parameters. RESULTS:The T allele was predominant in the study population with a frequency of 93%. No statistically significant difference was however observed between the genotypic (p?=?0.50) and allelic frequencies (p?=?0.58) of obese and non-obese subjects. Comparison of clinical and biochemical parameters of C allele carriers (CX?=?CC?+?CT) with those of TT genotype showed that there was no significant difference between the lipid profile of these two groups. CONCLUSION:The rs7903146 (C/T) polymorphism of the TCF7L2 gene might not be associated with obesity in the Cameroonian population.
Project description:Background:The emerging renal and cardiovascular complications of type 2 diabetes (T2DM) genetics involves differently assembled gene variants including transcription factor 7-like 2 (TCF7L2) and peroxisome proliferator-activated receptor gamma 2 (PPARG2) polymorphisms. However, the relevance of these genes for complication prediction has not been extensively tested. Methods:We analyzed the SNP rs7903146 variants in TCF7L2 and PPARG2 gene polymorphisms for their contribution to the incidence of chronic kidney disease (CKD) and cardiovascular complications in a prospective cohort study. All T2DM patients were followed up to estimate the glomerular filtration rate and cardiovascular outcomes. Cox proportional hazards regression models were used to estimate the genotype effect on the incidence of CKD and vascular complications. Results:A total of 422 patients were included. SNP rs7903146 variants in the TCF7L2 gene were classified into 3 groups: CC, 385 patients (91.2%), CT, 32 patients (7.6%), and TT, 5 patients (1.2%), while in the PPARG2 gene they were classified into 2 groups: Pro12Pro, 404 patients (95.7%) and Pro12Ala, 18 patients (4.3%). The prevalence of CKD, cardiovascular disease, and death at the end of the 5-year follow-up was 16.8, 29, and 7.9%, respectively. The Pro12Ala variant of the PPARG2 gene was significantly associated with increased CKD risk at the end of the study (adjusted HR 3.45, 95% CI 1.01-11.77, p = 0.046); it showed a significant association with increased cerebrovascular risk, but not cardiovascular disease and mortality. No genotype effect of rs7903146 in the TCF7L2 gene was apparent on renal and cardiovascular complications, except the TT variant of rs7903146 increased cardiovascular events when compared with the non-TT variant. Conclusion:The findings of our study were that the Pro12Ala variant in the PPARG2 gene was associated with risk of developing CKD and cerebrovascular disease in Asian T2DM subjects in a prospective cohort study. The TCF7L2 polymorphism was not associated with cardiovascular outcomes.
Project description:The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.
Project description:Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.
Project description:In this work we studied association of common variants in transcription factor 7-like 2 (TCF7L2) and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) genes with type 2 diabetes mellitus (T2DM) in Egyptians. Subjects and methods:This is a case-control study; 180 T2DM patients and 210 control subjects were genotyped for TCF7L2 rs7903146 and rs12255372 and CDKAL1 rs7756992 single nucleotide polymorphisms (SNPs) by TaqMan method on real time polymerase chain reaction system (real time-PCR). Results:TCF7L2 rs12255372 and rs7903146 associated with T2DM (p = 0.0001 and 0.003; respectively). The rs12255372 variant T allele associated with 2-fold increased risk for T2DM and TT genotype carriers were at 3.58-folds higher risk to develop T2DM than wild genotype (GG) carriers. Meanwhile, rs7903146 variant T allele associated with 1.6-fold increased risk for T2DM and TT genotype carriers were at 2.3-folds higher risk than wild genotype (CC) carriers. Both TCF7L2 SNPs significantly associated with T2DM under additive and dominant models and after adjustment for other covariates. On the other hand, CDKAL1 rs7756992 showed no significant association with T2DM under any genetic model. Both TCF7L2 SNPs were in strong LD (P = 0.02; D' = 0.85). Taking common TCF7L2 rs12255372/rs7903146 GC haplotype as reference, multivariate analysis confirmed the association of rs12255372 T allele-containing haplotypes (TC and TT) with T2DM. Haplotype TC associated with 6.32 times-higher risk for T2DM (95%CI = 0.55-76.17, Pc = 0.04) followed by haplotype TT which associated with 3.88 times-higher risk for the disease (95%CI = 1.09-13.76, Pc = 0.03). Conclusion:TCF7L2 rs12255372 and rs7903146 common variants associate with T2DM risk in Egyptians.
Project description:The present study examines cognitive function among transcription factor 7-like 2 (TCF7L2) genotype groups in a sample of older adults with cardiovascular disease.We recruited 111 older adults with diagnosed cardiovascular disease from outpatient cardiology clinics. Neuropsychological tests assessed the following domains of cognitive functioning: global function, attention/executive/psychomotor speed, learning and memory, visuospatial/construction, motor, and language. Genotyping of TCF7L2 single nucleotide polymorphism rs7903146 was conducted to determine membership in the TT, CT, or CC genotype groups.Controlling for diabetes status, participants with the TT genotype of TCF7L2 (n= 12) performed worse on tests of attention/executive function/processing speed than those with the CC (n= 46) and CT (n= 53) genotypes, despite no between-group differences in demographic or medical variables.Older cardiovascular disease patients with the TCF7L2 TT genotype performed worse on tests of attention/executive/ psychomotor speed than CC and CT genotype carriers. Further work using neuroimaging and glucose tolerance indices is needed to clarify underlying mechanisms.
Project description:The rs7903146-T allele in the transcription factor 7-like 2 (TCF7L2) gene has been associated with impaired pancreatic insulin secretion, enhanced liver glucose production, and an increased risk of type 2 diabetes. Nevertheless, the impact of rs7903146 on daily glucose trajectories remains unclear. Continuous glucose monitoring (CGM) can estimate glycemia and glycemic variability based on consecutive glucose measurements collected over several days. The purpose of the present study was to investigate the associations of rs7903146 with glycemia and glycemic variability in middle-aged participants without diabetes.Complete data from 235 participants without diabetes from the Leiden Longevity Study were available. Participants were divided into two groups based on rs7903146 genotype; rs7903146-CC genotype carriers (N = 123) and rs7903146-CT/TT genotype carriers (N = 112). Validated parameters of glycemia (e.g., mean 24h glucose level) and glycemic variability (e.g., 24h standard deviation) were derived from data collected with a CGM system for a 72-hour period.The study population was on average 64.7 years old (standard deviation = 5.9) and composed of 49.8% of women. Compared with rs7903146-CC carriers, rs7903146-CT/TT carriers exhibited a trend towards a higher mean 24-hour glucose level (5.21 versus 5.32 mmol/L; p-value = 0.15) and a significantly higher mean nocturnal glucose (3:00am- 6:00am; 4.48 versus 4.67 mmol/L; p-value = 0.03) that was explained for 34.6% by body weight and percentage body fat. No differences in measures of glycemic variability between the genotype groups were observed.Despite limited sample size, our study indicates that the rs7903146-T allele in TCF7L2 was associated with a higher mean nocturnal glucose dependent on body composition, which might suggest that rs7902146 affects liver-specific aspects of glucose metabolism.
Project description:Background:Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and reduces blood glucose in type 2 diabetes mellitus (T2DM). TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity. Objectives:To evaluate the postprandial pancreatic hormone response in patients with T2DM carriers of the TCF7L2 variant rs7903146 (CT/TT) compared with noncarriers of this variant (CC) after treatment with the GLP-1 agonist exenatide. Methods:Intervention study. Patients with T2DM (n?=?162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism (SNP). Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C (HbA1c), HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon before and after treatment with exenatide for 8 weeks. Results:Patients with genotypes CC and CT/TT presented similar glucose area under the curve (AUC) 0-180 min before treatment and a similar decrease after treatment (p?<?0.001). Before exenatide, insulin levels at 30-120 min were higher in CT/TT versus CC subjects (p?<?0.05). After treatment with exenatide, only CT/TT individuals demonstrated insulin reduction at 30-180 min during the meal test (p?<?0.05). Patients with the CC genotype presented no differences in insulin concentrations before and after treatment. The areas under the glucagon curve between 0 and 180 min were similar before treatment and reduced after treatment in both groups (p?<?0.001). Conclusions:The presence of the TCF7L2 rs7903146 T allele in patients with T2DM was associated with increased secretion of insulin response to a mixed-meal test. Furthermore, after treatment with exenatide, only the carriers of the T allele showed significantly decreased postprandial plasma insulin peak levels comparing with non carriers.