The TCF7L2 locus and type 1 diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Qu HQ
PROVIDER: S-EPMC1978206 | biostudies-literature | 2007
REPOSITORIES: biostudies-literature
Publications
The TCF7L2 locus and type 1 diabetes.
Qu Hui-Qi HQ Polychronakos Constantin C
BMC medical genetics 20070803
<h4>Background</h4>TCF7L2 belongs to a subfamily of TCF7-like HMG box-containing transcription factors, and maps to human chromosome 10q25.3. A recent study identified genetic association of type 2 diabetes (T2D) with this gene, correlated with diminished insulin secretion. This study aimed to investigate the possibility of genetic association between TCF7L2 and type 1 diabetes (T1D).<h4>Methods</h4>The SNP most significantly associated with T2D, rs7903146, was genotyped in 886 T1D nuclear famil ...[more]
Similar Datasets
Project description:Over the past ?15 years there has been great progress in our understanding of the genetics of both type 1 diabetes and type 2 diabetes. This has been driven principally by genome-wide association studies (GWAS) in increasingly larger sample sizes, where many distinct loci have now been reported for both traits. One of the loci that dominates these studies is the TCF7L2 locus for type 2 diabetes. This genetic signal has been leveraged to explore multiple aspects of disease risk, including developments in genetic risk scores, genetic commonalities with cancer, and for gaining insights into diabetes-related molecular pathways. Furthermore, the TCF7L2 locus has aided in providing insights into the genetics of both latent autoimmune diabetes in adults and various presentations of type 1 diabetes. This review outlines the knowledge gained to date and highlights how work with this locus leads the way in guiding how many other genetic loci could be similarly used to gain insights into the pathogenesis of diabetes.
| S-EPMC6702598 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have repeatedly shown an association between non-coding variants in the TCF7L2 locus and risk for type 2 diabetes (T2D), implicating a role for cis-regulatory variation within this locus in disease etiology. Supporting this hypothesis, we previously localized complex regulatory activity to the TCF7L2 T2D-associated interval using an in vivo bacterial artificial chromosome (BAC) enhancer-trapping reporter strategy. To follow-up on this broad initial survey of the TCF7L2 regulatory landscape, we performed a fine-mapping enhancer scan using in vivo mouse transgenic reporter assays. We functionally interrogated approximately 50% of the sequences within the T2D-associated interval, utilizing sequence conservation within this 92-kb interval to determine the regulatory potential of all evolutionary conserved sequences that exhibited conservation to the non-eutherian mammal opossum. Included in this study was a detailed functional interrogation of sequences spanning both protective and risk alleles of single nucleotide polymorphism (SNP) rs7903146, which has exhibited allele-specific enhancer function in pancreatic beta cells. Using these assays, we identified nine segments regulating various aspects of the TCF7L2 expression profile and that constitute nearly 70% of the sequences tested. These results highlight the regulatory complexity of this interval and support the notion that a TCF7L2 cis-regulatory disruption leads to T2D predisposition.
| S-EPMC3349716 | biostudies-literature
Project description:OBJECTIVE:The 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 METHODS:We 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. RESULTS:The 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. CONCLUSIONS:In 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.
| S-EPMC5780048 | biostudies-literature
Project description:Background and aimsCommon non-coding variations within the TCF7L2 locus have a strong influence on type 2 diabetes (T2D) susceptibility through uncharacterised mechanisms. An islet-specific functional polymorphism has been identified, although this does not explain the association between genotype and gene expression in other cell types. This study sought to identify these other functional TCF7L2 variants.Methods and resultsAlternative splicing and gene expression from TCF7L2 was examined from peripheral blood mononuclear cells from 100 healthy Caucasians using two T2D-associated SNPs, rs7903146 and rs12255372. Electrophoretic mobility shift assays and luciferase reporter assays were performed with these SNPs and those in strong LD to determine potential SNP functionality. Individuals homozygous for rs7903146 and rs12255372 T2D risk alleles (TT/TT) expressed 2.6-fold greater levels of TCF7L2 mRNA compared to individuals homozygous for the non-risk alleles (CC/GG, p = 0.006), although differentially spliced TCF7L2 transcripts did not differ by T2D risk-associated genotype. From SNPs identified to be in strong LD with the T2D-associated SNPs, rs7903146 and rs12255372, five (rs4132670, rs4506565, rs7903146, rs7901695, rs17747324) demonstrated allele-specific binding in electrophoretic mobility shift assays (EMSA). In luciferase reporter assays, rs4132670 exhibited 1.3-fold higher levels of enhancer activity in the Huh7 cell line (p = 3.8 × 10(-5)) and 2-fold higher levels in a WiDr colon carcinoma cell line (p = 0.008).ConclusionsThese results suggest that rs4132670, located in a region of chromatin accessibility, is a non-tissue-specific candidate functional SNP that has the potential to play a role in TCF7L2 gene expression and T2D risk.
| S-EPMC3778915 | biostudies-literature
Project description:BACKGROUND:TCF7L2 is the strongest type 2 diabetes (T2D) locus identified to date, and evidence suggests it plays an important role in insulin synthesis, processing, and secretion. Dietary factors that increase the insulin demand might enhance the risk of T2D associated with TCF7L2 variants. OBJECTIVE:The objective was to determine whether the risk of T2D associated with TCF7L2 is modified by the glycemic load (GL), glycemic index (GI), cereal fiber content, and total carbohydrate content of the diet. DESIGN:T2D cases (n = 1140) and controls (n = 1915) from the Nurses' Health Study were genotyped for TCF7L2 (rs12255372). Dietary intake was assessed with a semiquantitative food-frequency questionnaire. RESULTS:Significant differences in odds ratios (ORs) of T2D associated with the TCF7L2 genotype between high and low strata of GL (P = 0.03) and GI (P = 0.05) were suggested. Compared with the GG genotype, multivariate-adjusted ORs (95% CI) of T2D associated with the TT genotype were 2.71 (1.64, 4.46) and 2.69 (1.64, 4.43) among individuals in the highest tertile of GL and GI, respectively. Corresponding ORs (95% CIs) among individuals in the lowest tertiles of GL and GI were 1.66 (0.95, 2.88) and 1.82 (1.11, 3.01). The risk of T2D associated with the TCF7L2 single nucleotide polymorphism did not significantly differ by cereal fiber or carbohydrate intake. CONCLUSION:Carbohydrate quality and quantity modified risk of T2D associated with TCF7L2, which suggests that changes in risk attributable to the TCF7L2 variant are magnified under conditions of increased insulin demand.
| S-EPMC2667467 | biostudies-literature
Project description:BackgroundVariants in the TCF7L2 have been shown to be associated with an increased risk for type 2 diabetes (T2D). Since the association with diabetes could be explained by effects on insulin secretion, we investigated whether patients with diabetes risk alleles at rs7903146 might have an altered hypoglycaemic response to sulfonylureas (SUs).MethodsWe recruited 189 patients with T2D being treated with SUs and determined the rs7903146 diabetes risk genotype. We used a logistic regression with secondary SU failure defined as an A1C ≥7.0% after 6 months of SU treatment.ResultsIn univariate regression analyses, TCF7L2 genotype was the only predictor of SU treatment failure. The rs7903146 T allele was significantly more frequent in the group of patients who failed to respond to SU (36%) than in the control group (26%) [P = 0.046; odds ratio (OR): 1.57 (1.01-2.45) in an additive mode of inheritance].ConclusionsOur data suggest that patients with diabetes risk alleles in TCF7L2 have an altered hypoglycaemic response to SUs resulting in earlier secondary failure.
| S-EPMC3051886 | biostudies-literature
Project description:Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been associated with type 2 diabetes in adults. However, it is not known whether TCF7L2 variation increases the risk of early onset type 2 diabetes. Using a case-control design, we examined whether the reported variants [rs12255372 (T/G) and rs7903146 (T/C)] are associated with type 2 diabetes in SEARCH for Diabetes in Youth study participants.Variants were genotyped in 694 non-Hispanic white (NHW) youth (86 cases, mean age 15.5 years, mean BMI 34.8; and 608 controls, mean age 14.4 years, mean BMI 22.3) and 545 African-American (AA) youth (154 cases, mean age 15.9, mean BMI 37; and 391 controls, mean age 14.8, mean BMI 23.8). Logistic regression adjusted for age, sex, BMI and West African ancestry.The association of the risk T allele with case/control status was different in AA and NHW youth (p?=?0.025). Among AA youth, each copy of the T allele (rs7903146) was associated with a 1.97-fold (1.37, 2.82) increased odds for type 2 diabetes (p?<?0.0001), after adjustment for age, sex, BMI and African ancestry. No significant association was detected in NHW youth (adjusted OR, 1.14; 0.73, 1.79).TCF7L2 variation is associated with an increased risk of early-onset type 2 diabetes among AA youth, and the association appears to be stronger in AA than NHW youth. This suggests potential different contributions of genetic and environmental factors to early-onset type 2 diabetes by race.
| S-EPMC3766323 | biostudies-literature
Project description:BACKGROUND:Large scale association studies have found a significant association between type 2 diabetes mellitus (T2DM) and transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146. However, the quality of data varies greatly, as the studies report inconsistent results in different populations. Hence, we perform this meta-analysis to give a more convincing result. METHODS:The articles, published from January 1st, 2000 to April 1st, 2017, were identified by searching in PubMed and Google Scholar. A total of 56628 participants (34232 cases and 22396 controls) were included in the meta-analysis. A total of 28 studies were divided into 4 subgroups: Caucasian (10 studies), East Asian (5 studies), South Asian (5 studies) and Others (8 studies). All the data analyses were analyzed by the R package meta. RESULTS:The significant association was observed by using the dominant model (OR?=?1.41, CI?=?1.36?-?1.47, p?<?0.0001), recessive model (OR?=?1.58, CI?=?1.48?-?1.69, p?<?0.0001), additive model(CT vs CC) (OR?=?1.34, CI?=?1.28-1.39, p?<?0.0001), additive model(TT vs CC) (OR?=?1.81, CI?=?1.69-1.94, p?<?0.0001)and allele model (OR?=?1.35, CI?=?1.31-1.39, p?<?0.0001). CONCLUSION:The meta-analysis suggested that rs7903146 was significantly associated with T2DM in Caucasian, East Asian, South Asian and other ethnicities.
| S-EPMC5842570 | biostudies-literature
Project description:The transcription factor 7-like 2 gene (TCF7L2) rs7903146 T allele is constantly associated with Type 2 diabetes in various populations and ethnic groups. Nevertheless, this has not been observed in two studies involving Arab populations. The aim of the present study was to investigate the association between TCF7L2 rs7903146 in an Iranian population. Type 2 diabetes patients (N = 258) and normal healthy control subjects (N = 168) from the same area, were examined. The ARMS- PCR (Amplification Refractory Mutation System) technique, subsequently validated by direct sequencing, was used for genotyping. Allele and genotype frequencies were significantly different between patients and controls TT vs. CT + CC [p 0.0081 OR 3.4 95%CI (1.27-11.9)] and T vs. C allele [p 0.02 OR 1.4 95%CI (1.03-1.9)]. Our data thus confirm the association between the rs7903146 T allele and T2D in an Iranian population, contrary to previous reports in Arab populations. This can possibly be attributed to differences in ethnic background or the effects of environmental factors.
| S-EPMC3036108 | biostudies-literature
Project description:The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, regulating gene expression. It was initially identified in cancer research and embryologic developmental studies. Later, the TCF7L2 gene was linked to type 2 diabetes (T2D), implicating TCF7L2 and Wnt-signaling in metabolic disorders and homeostasis. In fact, TCF7L2-T2D variants confer the greatest relative risk for T2D, unquestionably predicting conversion to T2D in individuals with impaired glucose tolerance. We aim to describe the relevance of TCF7L2 in other human disorders. The TCF7L2-single nucleotide polymorphisms (SNPs) and T2D-risk association have been replicated in numerous follow-up studies, and research has now been performed in several other diseases. In this article, we discuss common TCF7L2-T2D variants within the framework of their association with human diseases. The TCF7L2 functional regions need to be further investigated because the molecular and cellular mechanisms through which TCF7L2 contributes to risk associations with different diseases are still not fully elucidated. In this review, we show the association of common TCF7L2-T2D variants with many types of diseases. However, the role of rare genetic variations in the TCF7L2 gene in distinct diseases and ethnic groups has not been explored, and understanding their impact on specific phenotypes will be of clinical relevance. This offers an excellent opportunity to gain a clearer picture of the role that the TCF7L2 gene plays in the pathophysiology of human diseases. The potential pleiotropic role of TCF7L2 may underlie a possible pathway for comorbidity in human disorders.
| S-EPMC9292842 | biostudies-literature