Transcription Factor 7-like 2 Variants Research Articles

Haplotype-based association study of TCF7L2 gene variants with the development of diabetic retinopathy in an Iranian population

ABSTRACT Background Diabetic retinopathy (DR) is recognized as one of the most prevalent complications of diabetes and a major cause of morbidity. Transcription factor 7-like 2 (TCF7L2), a pivotal component in the Wnt-signaling pathway, plays a significant role in β-cell development, blood-glucose homeostasis, cell survival, cell migration, and cell proliferation. Thus, this study aimed to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs12255372) with DR in a population-based association study. Materials and Methods DNA was extracted from whole blood of all subjects by salting-out procedure. Total 524 T2DM patients including 234 T2DM individuals without DR and 290 T2DM individuals with DR were genotyped by TaqMan assay technology. Clinical characteristics of subjects were conducted to evaluate the plausible association between TCF7L2 variants and DR with univariate linear regression analysis. Results Demographic analysis between case and control groups revealed significant differences in FBS, HbA1c, lipidemia, heart disease, and family history of T2DM (p < 0.05). No significant difference was observed in either genotypes distribution or allele frequency (p > 0.05) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed no significant association. Result of analysis indicated that HbAlc with adjusted OR of 1.8 (p < 0.0001) and first-degree relatives of family history with adjusted OR of 3.04 (p < 0.0001) were significantly associated with DR. Finally, haplotype analysis showed no noticeable association. Conclusion In conclusion, there was no significant genetic association between rs7903146, rs11196205, and rs12255372 with DR among T2DM Iranians; however, these variants may play unknown roles in other populations.

Association of common variants of TCF7L2 and PCSK2 with gestational diabetes mellitus in West Bengal, India

The genetic etiology of gestational diabetes mellitus (GDM) was suggested to overlap with type-2 diabetes(T2D). Transcription factor 7-like 2 (TCF7L2) and Proprotein Convertase Subtilisin/Kexin type 2 (PCSK2) are T2D susceptibility genes of the insulin synthesis/processing pathway. We analyzed associations of TCF7L2 and PCSK2 variants with GDM risk and evaluated their potential impact on impaired insulin processing in an eastern Indian population. The study included 114 GDM (case) and 228 non-GDM pregnant women (control). rs7903146, rs4132670, rs12255372 of TCF7L2, and rs2269023 of PCSK2 were genotyped by PCR-RFLP, and genotype distributions were compared between case and control. Fasting serum proinsulin and C-peptide levels were measured by ELISA and the Proinsulin/C-peptide ratio was considered an indicator of proinsulin conversion. Significantly higher frequency of risk allele (T) of rs12255372 (p = 0.02, OR = 2.0, 95%CI = 1.11–3.64) and rs4132670 (p = 0.002, OR = 2.26, 95%CI = 1.32–3.87) of TCF7L2 was found in GDM cases than non-GDM controls; TT genotype was associated with significantly increased disease risk. In rs7903146 (TCF7L2) and rs2269023 (PCSK2), although the frequency of risk allele (T) was not significantly higher in cases than controls, an association of TT for both variants remained significant with higher GDM risk in the recessive model. Increased serum pro-insulin and proinsulin:c-peptide ratio was found in GDM than non-GDM women and the phenomenon showed significant association with careers of risk alleles for TCF7L2 variants. In conclusion, TCF7L2 and PCSK2 variants are related to GDM risk in the studied population and hence may serve as potential biomarkers for assessing the disease risk. TCF7L2 variants contribute to impaired insulin processing.

Novel linkage and association of TCF7L2 variants with PCOS in Italian families.

Transcription factor 7-like 2 (TCF7L2) gene variants confer risk for type 2 diabetes and metabolic traits. We investigated the role of TCF7L2-variants in polycystic ovarian syndrome (PCOS), which is a common endocrine metabolic disorder affecting women of reproductive age. We tested whether TCF7L2 variants are in linkage to and/or in linkage disequilibrium [(LD), namely linkage and association)] with PCOS. Within 212 families from the Italian peninsular population, we analyzed 78 variants using Pseudomarker software for linkage to and LD with PCOS under the dominant model with complete penetrance (D1). In a secondary analysis, we tested the variants under the recessive models with complete penetrance (R1), dominant with incomplete penetrance (D2), and recessive with incomplete penetrance (R2). We tested through in silico analysis the risk variants to detect any potential functional effects. We identified a total of 14 variants in the TCF7L2 gene significantly linked to and/or in LD with the risk of PCOS (p < 0.05) across different models. This study is the first to report TCF7L2 linkage and linkage disequilibrium in Italian families with PCOS.

Effects of the TCF7L2 and KCNQ1 common variant on sulfonylurea response in type 2 diabetes mellitus patients: a preliminary pharmacogenetic study.

Type 2 diabetes mellitus (T2DM) is a common chronic condition characterized by high blood glucose levels which is caused by genetic and environmental factors. Currently, pharmacogenomics (PGx) is anticipated to enable the development of personalized treatment in a wide range of health issues.Sulfonylureas (SFUs) are among the oral anti-diabetic drugs that are very popular due to their low cost. Genetic variants in transcription factor 7 like 2 (TCF7L2) and potassium voltage-gated channel subfamily Q member 1 (KCNQ1) have been reported for altered therapeutic response to sulfonylurea. The aim of the present study is to evaluate any association between common genetic variant of the TCF7L2 and KCNQ1 (rs7903146 and rs2237892, respectively) and the response to sulfonylurea in a group of Iranian patients for the first time. Genotyping was carried out in 30 T2DM patients who received sulfonylurea treatment for more than two months in addition to previous medication using the Sanger sequencing method. In 30 T2DM patients who received SFUs treatment, 60%, 33.3% and 6.7% had CC, CT and TT genotypes, respectively. After treatment, adjusted fasting blood sugar (FBS) mean reduction level in CT and TT carriers was lower than CC carriers. Adjusted hemoglobin A1c (HbA1c) mean reduction level was also lower in CT and TT compared with CC carriers, but, none of these differences were statistically significant.Genotype frequencies of TT, CT and CC genotypes of rs2237892 variant of KCNQ1 gene were 0 (0%), 3 (10%) and 27 (90%) respectively. Patients with CT and CC genotypes of rs2237892 variant had also similar changes in FBS (P=0.200) and HbA1c (P=0.436) after treatment with SFUs. Genotypes of TCF7L2 and KCNQ1 common variant did not show any impact on the treatment response among T2DM patients receiving SFUs.

Lifestyle Modifications on the Expression of TCF7L2 Gene Polymorphism: A Cross-sectional Study

Introduction: Type 2 Diabetes Mellitus (T2DM) is the result of the clustering of factors along with the communication between environmental factors and a strong hereditary component. In this modern age of investigation, molecular mechanisms of Transcription Factor 7 Like 2 (TCF7L2) linking with the physiological functioning in pancreatic and intestinal endocrine cells are explored. Hitherto few studies have been done in the Indian population with regard to gene polymorphism in TCF7L2 and T2DM concerning family history. Aim: To study effect of lifestyle modifications on the expression of TCF7L2 gene polymorphism in subjects with family history of diabetes. Materials and Methods: This was a cross-sectional study, conducted over a period of 14 months September 2020 to November 2021) with 121 subjects from Shimoga district at Shimoga Institute of Medical Sciences, Shivamogga, Karnataka, India. The study was conducted after the approval by the Ethics Committee and subjects volunteering for the study have signed the informed consent. The study comprised of two groups. Both the groups had family history of T2DM, eventually persons who had not developed diabetes and had changed their lifestyle were grouped I (n=56) and subjects who had developed diabetes without any changes in their lifestyle were considered as group II (n=65). Fasting insulin, and fasting blood glucose was estimated along with the anthropometric variables like height, weight, waist circumference, hip circumference. Two Single Nucleotide Polymorphism (SNP) (rs7903146 and rs1225372) of TCF7L2 gene was genotyped using Tetra-primer Amplification Refractory Mutation System (T-ARM) protocol. Differences in clinical parameters and genotypic variants between groups, was calculated using the independent t-test and Chi-square test, a p value of &lt;0.05 was considered statistically significant. Results: Only fasting insulin and WHR Waist Hip Ratio (WHR) parameters were weakly significant in the study population. The risk allele frequency (T) was seen to be higher in the group I and the chances of getting diabetics was 2.02 times higher than the subjects of group II for rs7903146. This substantiates that the group I subjects were more predisposed to diabetes genetically. Since subjects with heterozygous genotype (CT or GT alleles) has been associated with the highest risk of developing T2DM, the association of heterozygous genotype was high in the group with lifestyle modification and was highly significantly associated with risk of being diabetic by 7.50 times for rs7903146 and 6.10 times for rs1225372. Further risk analysis of variants according to a model of inheritance was analysed and was observed that the co-dominant and overdominant models best fitted the association with an OR above 6 for both the polymorphism. Conclusion: This study depicts that lifestyle modification masks the effect of risk variants for rs12255372 and rs7903146. The confounding nature of the influence of environmental factors over predisposition to inheritance is well depicted for the manifestation of T2DM among the genetic variants of TCF7L2.

Transcription factor 7-like 2 (TCF7L2): a culprit gene in Type 2 Diabetes Mellitus

The genetics of Type 2 diabetes a complex metabolic disorder, characterized by decreased insulin secretion and insulin resistance resulting in impaired blood glucose homeostasis remains enigma for geneticists. In 2006 an important step while finding genetic causes of diabetes type 2 was identification of transcription factor 7-like 2 (TCF7L2) gene an important marker in predisposition of type 2 diabetes in almost all ethnic population. Recent genetic research identifies numerous novel type 2 diabetes susceptible genes among these genes TCF7L2 is considered as gang head and emerged as the most promising types 2 diabetes causing gene. Risk variants in TCF7L2 effects pancreatic beta cell development and insulin secretion by influencing Wnt Signaling pathway. Genetic variants in TCF7L2 confer risk for type 2 diabetes by altering expression of transcription factor (which has key role in blood glucose regulation) in pancreas. The purpose of this paper is to evaluate type 2 diabetes susceptible gene the TCF7L2 and to present a comprehensive review of studies carried out worldwide in different ethnic population on association of TCF7L2 polymorphism with type 2 diabetes.

TCF7L2 rs7903146 Is Associated With Increased Risk of New-Onset Diabetes After Transplant: A Meta-analysis of Literature

Single nucleotide polymorphisms may influence the risk of development of new-onset diabetes after transplant (NODAT), a post-transplant clinical complication that is often implicated in allograft rejection and mortality. We performed a meta-analysis of association between transcription factor 7-like-2 (TCF7L2) rs7903146 and risk of NODAT. A systematic search was conducted using PubMed and ScienceDirect electronic databases for studies published between January 2001 and January 2021. Case-control or cohort studies reporting association between NODAT (diagnosis based on American Diabetes Association criteria) and TCF7L2 rs7903146 were included. MetaGenyo was used for meta-analysis (random-effects model). Pooled odds ratios with 95% confidence intervals were reported to evaluate the strength of association. Two reviewers independently screened for articles. A total of 6 case-control studies were included for full-text review and quantitative analysis after screening for eligibility. Genotypic distributions were in Hardy-Weinberg equilibrium for included studies. All articles reported statistically significant association of TCF7L2 rs7903146 for risk of NODAT except for 1 study. There was moderate heterogeneity among studies (I2=60.6%). Pooled analysis revealed 51% odds of developing NODAT with TCF7L2 rs7903146 T allele (allele contrast model: odds ratio, 1.51; 95% confidence interval, 1.13-2.02; P=.005). The present meta-analysis demonstrated association between TCF7L2 variant rs7903146 and risk of developing NODAT. This finding suggest clinical implications for individuals undergoing kidney transplant.

Фактор транскрипции 7 (TCF7L2): фактор риска развития сахарного диабета 2 типа

The genetics of Type 2 diabetes a complex metabolic disorder, characterized by decreased insulin secretion and insulin resistance resulting in impaired blood glucose homeostasis remains enigma for geneticists. In 2006 an important step while finding genetic causes of diabetes type 2 was identification of transcription factor 7-like 2 (TCF7L2) gene an important marker in predisposition of type 2 diabetes in almost all ethnic population. Recent genetic research identifies numerous novel type 2 diabetes susceptible genes among these genes TCF7L2 is considered as gang head and emerged as the most promising types 2 diabetes causing gene. Risk variants in TCF7L2 effects pancreatic beta cell development and insulin secretion by influencing Wnt Signaling pathway. Genetic variants in TCF7L2 confer risk for type 2 diabetes by altering expression of transcription factor (which has key role in blood glucose regulation) in pancreas. The purpose of this paper is to evaluate type 2 diabetes susceptible gene the TCF7L2 and to present a comprehensive review of studies carried out worldwide in different ethnic population on association of TCF7L2 polymorphism with type 2 diabetes.

Association of Combined TCF7L2 and KCNQ1 Gene Polymorphisms with Diabetic Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus.

BackgroundVascular complications are the major morbid consequences of type 2 diabetes mellitus (T2DM). The transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) are common T2DM susceptibility genes in various populations. However, the associations between polymorphisms in these genes and diabetic complications are controversial. This study aimed to investigate the effects of combined gene-polymorphisms within TCF7L2, KCNQ1, and KCNJ11 on vascular complications in Thai subjects with T2DM.MethodsWe conducted a case-control study comprising 960 T2DM patients and 740 non-diabetes controls. Single nucleotide polymorphisms in TCF7L2, KCNQ1, and KCNJ11 were genotyped and evaluated for their association with diabetic vascular complications.ResultsThe gene variants TCF7L2 rs290487-T, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-C were associated with increased risk of T2DM. TCF7L2 rs7903146-C, TCF7L2 rs290487-C, KCNQ1 rs2237892-T, and KCNQ1 rs2237897-T revealed an association with hypertension. The specific combination of risk-alleles that have effects on T2DM and hypertension, TCF7L2 rs7903146-C, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-T, as genetic risk score (GRS), pronounced significant association with coronary artery disease (CAD), cumulative nephropathy and CAD, and cumulative microvascular and macrovascular complications (respective odds ratios [ORs] with 95% confidence interval [95% CI], comparing between GRS 2–3 and GRS 5–6, were 7.31 [2.03 to 26.35], 3.92 [1.75 to 8.76], and 2.33 [1.13 to 4.79]).ConclusionThis study demonstrated, for the first time, the effect conferred by specific combined genetic variants in TCF7L2 and KCNQ1 on diabetic vascular complications, predominantly with nephropathy and CAD. Such a specific pattern of gene variant combination may implicate in the progression of T2DM and life-threatening vascular complications.

Genetic polymorphisms in TCF7L2 and PPARG genes and susceptibility to Type 2 diabetes mellitus

Transcription factor 7-like 2 (TCF7L2) plays an important role in insulin resistance and peroxisome proliferator-activated receptor γ (PPARG) is directly targeted by antidiabetic drug. This study was designed to investigate the association of genetic variants in TCF7L2 and PPARG and T2DM susceptibility. Blood samples were collected from 472 subjects (221 controls and 251 T2DM cases) after ethical approval. All subjects were genotyped for two single nucleotide polymorphisms (SNPs) in each gene TCF7L2 (+9017G>T and -41435C>T) and PPARG (-44458C>G, -17676A>G) using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) and amplification-refractory mutation system (ARMS-PCR). The TCF7L241435C>T polymorphism showed significantly higher frequency of 'TT' genotype in controls (12.2%) (P = 0.023). Haplotype 'GC*' of TCF7L2 (+9017G>T,-41435C>T) showed significant association with T2DM (P = 0.043). We conclude that individuals with 'GTG*' allelic combination were at significantly higher risk for T2DM (OR = 5.1, P=0.0002 respectively) whereas GCG* and GTA* allelic combinations showed significant protection against T2DM.The individual SNPs in TCF7L2 and PPARG genes were non-informative in genotyping analysis but showed significant risk for T2DM when analyzed together.

A Reduced Incretin Effect Mediated by the rs7903146 Variant in the TCF7L2 Gene Is an Early Marker of β-Cell Dysfunction in Obese Youth.

The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT - AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [-7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.

4363 TCF7L2 variants in African American patients with bipolar disorder and high BMI

OBJECTIVES/GOALS: In a previous genome-wide association study of European Americans, rs12772424, a variant in the gene encoding transcription factor 7-like 2 (TCF7L2), was shown to have a SNP-BMI interaction association with bipolar disorder (BD). The objective of this study was to replicate this finding in an African American (AA) sample. METHODS/STUDY POPULATION: Using a sample of 659 controls and 323 BD cases from the Genetic Association Information (GAIN) Study of BD, we conducted analyses to assess association between BD and the interaction of BMI with genetic variation in TCF7L2. For this study we identified 4572 single nucleotide polymorphisms (SNPs) in a 1Mb region around the candidate SNP rs1272424. Based on variants identified in the prior analysis of the larger European American dataset we selected SNPs for analysis in the AA data. This allowed for a smaller AA sample, and still maintained adequate power for statistical significance. RESULTS/ANTICIPATED RESULTS: We anticipate observing an effect of TCF7L2 variation on the relationship between BD and BMI in the AA data. We also anticipate that combining results from the European and African American patients may help narrow down potentially functional variants in TCF7L2 that influence the association between BD and BMI. DISCUSSION/SIGNIFICANCE OF IMPACT: Psychiatric genetics studies lack ancestral diversity among participants, decreasing their generalizability, and possibly increasing health disparities, especially for diseases like BD, which is often misdiagnosed and untreated in AAs. This work propels us towards understanding the genetics of BD and obesity in this underrepresented population.

Single and multi-locus association study of TCF7L2 gene variants with susceptibility to type 2 diabetes mellitus in an Iranian population

Prior studies indicated that some of transcription factor 7-like 2 (TCF7L2) gene variants such as rs7903146, rs12255372 and rs11255372 are constantly associated with Type 2 diabetes mellitus (T2DM) in various populations and ethnic groups. The purpose of this study was to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs11255372) and T2DM by TaqMan assay. Statistical analysis was performed through SNPAlyze and SPSS. Significant associations of rs7903146 (P = 1.9 × 10–7), and rs11255372 (P = 2.98 × 10–10) both under a dominant model were found. Based on allele frequency, there was a significant difference between the two study groups at rs7903146 and rs12255372 variants (P = 6.8 × 10–10, and P = 9.3 × 10–11, respectively). Two haplotypes including Hap-1 (C-G-G) and Hap-2 (T-G-T) indicated a significant difference between the two study groups (P = 1.174 × 10-9and P = 7.432 × 109 respectively). In conclusion, rs7903146 and rs12255372 were significantly associated with T2DM in the specified Northern Iranian population.

Contribution of single-nucleotide polymorphism in transcription factor 7-like 2 gene to cardiometabolic risk in adult Nigerians

Background: Single-nucleotide polymorphism in the gene, transcription factor 7-like 2 (TCF7L2), shows the strongest and most consistent association with risk of developing type 2 diabetes (T2D). TCF7L2 has been associated with both impaired beta-cell function and insulin resistance. Gene variants of TCF7L2 may, therefore, contribute to cardiometabolic risk (CMR) and metabolic syndrome (MS). Aims and Objectives: The study aims to examine the relationship between gene variants in TCF7L2 with MS and CMR. Methods: Three hundred and fifty-six adult Nigerians aged between 40 and 100 years participated in a cross-sectional, analytical study. The association between TCF7L2 genotypes and MS and its components was determined. The data were analyzed, and statistical significance was set at P Results: Three hundred and fifty-six individuals participated in the study (35.6% of males and 64.2% of females). About 64.9% of participants had T2D. The prevalence of MS was 26.4%. Among the individuals with the wild-type homozygote genotype CC, heterozygote genotype CT, and homozygote mutant TT, 24.9%, 27.2%, and 30.6% had MS, respectively. The risk T allele was associated with higher mean values of waist circumference and triglyceride than the C allele (P = 0.006 and 0.022, respectively). The T allele had a significant correlation with MS components (P Conclusion: Variants in the TCF7L2 gene are associated with components of MS and correlate with CMR through insulin resistance.

Role of TCF7L2 and PPARG2 Gene Polymorphisms in Renal and Cardiovascular Complications among Patients with Type 2 Diabetes: A Cohort Study

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.

TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome.

Transcription factor 7-like 2 (TCF7L2) gene variants rs12255372 and rs7903146 have been consistently shown to raise genetic risk for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the possible role of these variants in the development of impaired glucose metabolism (IGM), including impaired fasting glucose (IFG) or T2DM, in patients with metabolic syndrome (MS). The study population consisted of 228 patients with MS who were divided into two groups. The first group consisted of 148 patients with MS and IGM [39M/109F, 59.8 ± 14.6 (mean ± SD) years] and the second group of 80 patients with MS and normoglycemia (NGM) (16M/64F, 56.1 ± 15.8years). The diagnosis of MS was based on the criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) Scientific Statement. Anthropometric parameters including BMI and waist circumference were recorded and blood samples were obtained after overnight fasting for biochemical tests. The rs12255372 and rs7903146 TCF7L2 polymorphisms were genotyped in peripheral blood leucocytes. Analysis of the distribution of the TCF7L2 polymorphic alleles revealed that the frequency of the T allele of the TCF7L2 variant rs12255372 was 38.2% in the study population, while the frequency of the T allele of the TCF7L2 rs7903146 variant was 35.3%. The T allele of the rs12255372 variant was more frequently present in patients with MS and IGM (48.3%) compared to patients with MS and NGM (19.4%, p < 0.001). Also, the T allele of rs7903146 was more frequently present in patients with MS and IGM (44.6%) compared to patients with MS and NGM (18.1%, p < 0.001). Logistic regression analysis followed and revealed that the presence of the T allele for both rs12255372 and rs7903146 TCF7L2 gene variants is a very powerful predictor of the presence of glucose disorders, increasing the risk more than fourfold in patients with MS and after adjustment for potential confounders, such as age, gender, BMI, and waist circumference (TCF7L2 rs12255372: Exp(B) 4.917, p < 0.001 and TCF7L2 rs7903146: Exp(B) 5.460, p < 0.001). The presence of the rs12255372 and rs7903146 TCF7L2 gene variants plays an important role in the development of T2DM among individuals with MS. These findings support the notion that among subjects with MS, those who finally develop T2DM have a genetic predisposition to β-cell dysfunction.

TCF7L2 Gene Polymorphisms and Susceptibility to Type 2 Diabetes Mellitus, A Pilot Study

Transcription factor 7-like 2 (TCF7L2) variants are known risk factors of type 2 diabetes (T2DM).However, this association is not consistent among different populations. The current study aimed at investigating the relationship between rs 7903146, rs 12255372 variants of TCF7L2 and susceptibility to T2DM and different metabolic parameters in a cohort of Egyptian type 2 diabetic patients. This case control study included 60 diabetic patients and 60 matched unrelated healthy controls. Genotyping was performed by using Real Time-PCR. The frequency of genotypes, alleles, anthropometric measures, glycemic indices, HOMA-IR and lipid profile were evaluated in patients and control. Regarding rs 7903146, TT genotype was more frequent in healthy controls (43.3%) than diabetic patients (20%) (OR = 0.291, 95% CI = 0.108-0.788, P = 0.015). T allele was more frequent in healthy control (61.7%) than diabetic patients (44.2%) and it was associated with lower risk of diabetes (OR = 0.492, 95% CI = 0.294-0.823, P = 0.007).However, there was no significant difference between patients with CC, CT and TT genotypes of rs7903146 regarding HbA1C (p=0.549), HOMA-IR (p=0.359), total cholesterol (p=0.482). In contrast, T allele of rs12255372 had no significant relation to diabetes risk (OR = 0.602, 95% CI = 0.361-1.005, P = 0.052). There was no statistically significant difference of frequency of any rs12255372 genotypes between cases and controls In addition, patients with GG,GT, TT genotypes of rs12255372 had no significant difference regarding HbA1C (p=0.393), HOMA-IR (p=0.985), total cholesterol (p=0.368). The study confirmed the association of TCF7L2 (rs 7903146) and T2DM, while failed to detect any association between TCF7L2 (rs 12255372) and susceptibility to T2DM. No significant difference in respect to metabolic parameters between different genotypes of rs7930146 and rs12255372.

TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes.

OBJECTIVEThe phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes–associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.RESEARCH DESIGN AND METHODSWe studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3–58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)–stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.RESULTSThe rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.CONCLUSIONSIn this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes–linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes–like pathogenic mechanisms.

Type 2 diabetes-associated genetic variants of FTO, LEPR, PPARg, and TCF7L2 in gestational diabetes in a Brazilian population.

Gestational diabetes mellitus (GDM) is a metabolic disorder that shares pathophysiologic features with type 2 diabetes mellitus. The aim of this study was to investigate the association of the polymorphisms fat mass and obesity-associated (FTO) rs1421085, leptin receptor (LEPR) rs1137100, rs1137101, peroxisome proliferator-activated receptor gamma (PPARg) rs1801282, and transcription factor 7-like 2 (TCF7L2) rs7901695 with GDM. 252 unrelated Euro-Brazilian pregnant women were classified into two groups according to the 2015 criteria of the American and Brazilian Diabetes Association: healthy pregnant women (n = 125) and pregnant women with GDM (n = 127), matched by age. The polymorphisms were genotyped using fluorescent probes (TaqMan®). All groups were in Hardy-Weinberg equilibrium. The genotype and allele frequencies of the studied polymorphisms did not show significant differences between the groups (P > 0.05). In the healthy and GDM groups, the C allele frequencies (95% CI) of the FTO rs1421085 polymorphism were 36.8% [31-43%] and 35.0% [29-41%]; the G allele frequencies (95% CI) of the LEPR rs1137100 polymorphism were 24.8% [19-30%] and 22.8% [18-28%]; the G allele frequencies (95% CI) of the LEPR rs1137101 polymorphism were 43.6% [37-50%] and 42.9% [37-49%]; the G allele frequencies (95% CI) of the PPARg rs1801282 polymorphism were 7.6% [4-11%] and 8.3% [5-12%]; and the C allele frequencies (95% CI) of the TCF7L2 rs7901695 polymorphism were 33.6% [28-39%] and 39.0% [33-45%], respectively. The studied polymorphisms were not associated with GDM in a Brazilian population.

Role of GNB3, NET, KCNJ11, TCF7L2 and GRL genes single nucleotide polymorphism in the risk prediction of type 2 diabetes mellitus.

Type 2 diabetes (T2DM) is a polygenic metabolic disorder characterized by hyperglycemia occurring as a result of impaired insulin secretion or insulin resistance. Various environmental and genetic factors interact and increase the risk of T2DM and its complications. Among the various genetic factors associated with T2DM, single nucleotide polymorphism in different candidate genes have been studied intensively and the resulting genetic variants have been found to have either positive or negative association with T2DM thereby increasing or decreasing the risk of T2DM, respectively. In this review, we will focus on Guanine nucleotide-binding protein subunit beta 3 (GNB3), Norepinephrine Transporter (NET), Potassium Channel gene (KCNJ11), Transcription Factor 7-Like 2 (TCF7L2) and Glucocorticoid receptor (GRL) genes and their association with T2DM studied in different ethnic groups. The products of these genes are involved in the biochemical pathway leading to T2DM. Polymorphisms in these genes have been intensively studied in individuals of different ethnic origins. Results show that genetic variants of TCF7L2 and KCNJ11 genes have potential to emerge as a risk biomarker for T2DM whereas results of GNB3, GRL and NET genes have been controversial when studied in individuals of different ethnicities. We have tried to summarize the results generated globally in context to the selected genes which could possibly help researchers working in this field and would eventually help in understanding the mechanistic pathways of T2DM leading early diagnosis and prevention.