Role Of TCF7L2 Research Articles

The Role of TCF7L2 in Type 2 Diabetes.

TCF7L2 is the most potent locus for type 2 diabetes (T2D) risk and the first locus to have been robustly reported by genomic linkage studies. TCF7L2 is a transcription factor that forms a basic part of the Wnt signaling pathway. This gene has highly conserved sequence regions that correspond to functional domains. The association of TCF7L2 with T2D is one of the most powerful genetically discovered in studies of complex diseases, as it has been consistently replicated in multiple populations with diverse genetic origins. The mechanisms over which TCF7L2 exerts its effect on T2D are still not well understood. In this article, we describe the main molecular mechanisms of how TCF7L2 is related to T2D. TCF7L2 variants associated with T2D risk exert an influence on the initial therapeutic success of the hypoglycemic oral agent sulfonylurea. Thus, it is important to know whether there are other TCF7L2 variants associated with T2D that can influence treatment with oral hypoglycemic agents. Resequencing of the TCF7L2 gene in diverse ethnic groups is required to reveal common and rare variations and their role in different pathologies and in adverse reactions to drugs. Identification of TCF7L2-susceptibility disease variants will permit, at a given moment, offering of therapies to patients according to their genotype.

TCF7L2 regulates postmitotic differentiation programmes and excitability patterns in the thalamus.

ABSTRACTNeuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2−/− embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.

1317-P: Static, but Nondynamic, ß-Cell Responsiveness to Glucose Is Affected by the Risk Variant rs7903146 of TCF7L2 and Associated with a Delayed Time-to-Glucose-Peak in Obese Youths

Background: Beta-cell function can be dissected into a dynamic component, estimating the immediate secretion after glucose change, and a static component representing the insulin secreted at any given glucose level. We evaluated their clinical and genetic determinants as well as their effect on glucose time to peak in obese youths. Methods: A 3hOGTT was performed in 630 obese youths (374F, 13.6±3.1y, 33.3±7.5kg/m2); dynamic (DId) and static (DIs) components of beta-cell function were estimated by the oral minimal model. Participants were genotyped for the rs7903146 of TCF7L2 and grouped into 3 tertiles for DId and DIs. Effect of sex, BMI, age, ethnicity and TCF7L2 on DIs/DId was estimated by multivariate regression model. Results: Lower DId, as well as DIs, were associated with higher BMI and 2h-glucose, while fasting glucose was increased in the lower DIs tertile. The risk genotype (TT) for the TCF7L2 and the BMI, were both associated to a lower DIs (p<0.01), while TCF7L2 did not affect DId (p=0.22). Glucose time to peak>30min was more likely in the lower DIs, without a difference among the DId tertiles (Figure). Conclusion: The risk variant of TCF7L2 is associated with a blunted DIs, in the absence of an effect on the DId, and accompanied by a delayed glucose time to peak. The role of TCF7L2 in the incretin response might be responsible for this effect. Disclosure A. Galderisi: None. D. Trico: None. C. Dalla Man: None. S. Siebel: None. N. Santoro: None. B. Pierpont: None. C. Cobelli: None. S. Caprio: None. Funding National Institutes of Health (R01DK085577-01, R01HD40787, R01HD28016, P30DK045735, K12DK094714-02, R01DK111038-01A1); Robert E. Leet and Clara Guthrie Patterson Trust; European Medical International Framework (EMIF115372)

T130. Transcriptome Profile in iPSC-Derived Astrocytes of TCF7L2, a Transcription Factor Associated With Bipolar Disorder, Reveals Relationship With Neural Function

Bipolar Disorder (BD) has been associated with multiple phenotypic traits, including obesity. We previously performed genome-wide association studies (GWAS) for BMI-dependent BD risk and identified a genome-wide significant SNP mapped to the TCF7L2 gene. This signal was replicated in an independent cohort. TCF7L2 encodes a transcription factor in the Wnt/beta-catenin pathway. Genetic polymorphisms in TCF7L2 have been associated with type-2 diabetes risk. However, the role of TCF7L2 in neuropsychiatric disorders like BD is not well understood.

Transcription Factor 7-like 2 (TCF7L2) rs7903146 Polymorphism, Association with Type 2 Diabetes Mellitus Susceptibility

Objectives: The aim of this study was to investigate the possible role of TCF7L2 rs 7903146 (C/T) variant on susceptibility of T2DM among Egyptian children and adolescents. Patients and methods: 30 T2DM pediatric patients, 20 obese children and 20 control subjects were enrolled in the study and subjected to: anthropometric measurements, routine laboratory studies including lipid profile, fasting serum insulin level and homeostatic model assessment of insulin secretion and β cell function. The rs7903146 (C/T) polymorphism was genotyped using the PCR-RFLP method. Results: T allele of TCF7L2 rs7 903146 (C/T) was associated with T2DM in the study (P<0.001; OR=5.96, 95% CI: (2.58-16.22). Haplotype analyses showed a higher distribution of haplotype TT in the T2DM patients than the control group [56.7% vs. 15.0%, P<0.002; χ2=11.66]. Association of TCF7L2 rs7903146 and clinical and metabolic measures in T2D patients revealed significantly lower levels of fasting insulin and Homa β among carriers of T allele. Also, no significant interaction was found between T2D risk and BMI (SDS) regarding rs7903146 SNP. Conclusion: Our data prove that rs7903146 (C/T) variant of the TCF7L2 gene is associated with T2DM in our study.

Association of the Type 2 Diabetes Mellitus Susceptibility Gene, TCF7L2, with Schizophrenia in an Arab-Israeli Family Sample

Many reports in different populations have demonstrated linkage of the 10q24–q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24–q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10−6) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10−6) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required.

Genotype and Tissue-Specific Effects on Alternative Splicing of the Transcription Factor 7-Like 2 Gene in Humans

Context: Noncoding single-nucleotide polymorphisms (SNPs) within the TCF7L2 gene are confirmed risk factors for type 2 diabetes, but the mechanism by which they increase risk is unknown. Objective: We hypothesized that associated SNPs alter TCF7L2 splicing and that splice forms have altered biological roles. Design: Splice forms and 5′ and 3′ untranslated regions were characterized in sc adipose, muscle, liver, HepG2 cells, pancreas, and islet. Isoform-specific transcript levels were quantified in sc adipose. Alternative splice forms were characterized in HepG2 liver cells under glucose and insulin conditions and in SGBS cells with differentiation. Major isoforms were characterized by transfection. Setting: The study was conducted at an ambulatory general clinical research center. Patients: Patients included 78 healthy, nondiabetic study subjects characterized for insulin sensitivity and secretion. Results: We identified 32 alternatively spliced transcripts and multiple-length 3′ untranslated region transcripts in adipose, muscle, islet, and pancreas. Alternative exons 3a, 12, 13, and 13a were observed in all tissues, whereas exon 13b was islet specific. Transcripts retaining exons 13 and 13a but not total TCF7L2 transcripts were significantly correlated with both obesity measures (P < 0.01) and rs7903146 genotype (P < 0.026) in sc adipose. Insulin (5–10 nM) suppressed all TCF7L2 isoforms in SGBS cells but suppressed exon 13a-containing isoforms most significantly (P < 0.001). The isoform distribution differed throughout SGBS cell differentiation. Isoforms with predicted early stop codons yielded stable proteins of the predicted size, bound β-catenin, and targeted correctly to the nucleus. Conclusions: Intronic TCF7L2 variants may regulate alternative transcript isoforms, which in turn may have distinct physiologic roles. a a a Page 1 of 16 Genotype and Tissue-Specific Effects on Alternative Splicing of the Transcription Factor ... 6/19/2014 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841530/?report=printable Type 2 diabetes (T2D) is among the common, complex diseases for which genetic predisposition is well accepted (1). Grant et al. (2) reported the association of single-nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2), and this association has been convincingly replicated as the strongest genetic risk factor for T2D (3). Nonetheless, the SNPs implicated are intronic (4) and are not associated with total TCF7L2 transcripts in adipose and muscle (5). Physiological studies of TCF7L2 risk variants have most consistently demonstrated reduced insulin secretion in large epidemiology studies (6,7,8), but other findings suggest a broader role consistent with widespread gene expression (5,9,10,11). TCF7L2 plays a key role in the Wnt signaling pathway (12) and may be important in the expansion and maintenance of β-cell mass (9). However, both increased and decreased TCF7L2 expression in β-cells has been associated with altered insulin secretion and apoptosis in human islets (11,13). Other studies suggested reduced glucagon-like peptide (GLP)-1 induced insulin secretion among carriers (14) or altered proinsulin processing (15). GLP-1 and GLP-1 agonists may act through TCF7L2 and the Wnt pathway to expand and maintain β-cell mass (12). Whereas recent data strongly support a role for TCF7L2 in the β-cell, the means by which intronic variants alter β-cell function or mass remain unclear. Wnt signaling is known to be important in other tissues, including adipose (16), and the proinflammatory cytokine TNFα may inhibit adipogenesis by way of β-catenin/TCF7L2 signaling (17). Studies from our laboratory and others supported a role for TCF7L2 SNPs in altered insulin sensitivity (10), but we and others (5) failed to find a genotype effect on total adipose TCF7L2 transcript levels (5,18,19). Reports of differences in TCF7L2 expression between visceral and sc adipose are inconsistent (18,20,21). The T2D-associated TCF7L2 variants are located in a linkage disequilibrium block that encompasses introns 3 and 4. The T allele of SNP rs7903146 showed reduced binding to protein factors in several cell lines (22), but the relevance of this finding to T2D risk is uncertain. Previous studies suggested multiple TCF7L2 splice forms in tumor tissue (23) and while this work was in preparation, tissue-specific splicing was confirmed in pancreatic islets, lymphocytes, skeletal muscle, and adipose tissue in nondiabetic human subjects (24,25). We hypothesized that TCF7L2 susceptibility variants act by altering the levels of specific transcript isoforms and that splice forms differ in biological function. We characterized the transcript isoforms and untranslated regions in human tissues relevant to diabetes and quantified isoform-specific transcript levels by genotype in nondiabetic subjects. To examine the physiological role of transcript isoforms, we examined the isoform distribution in response to glucose and insulin and during adipocyte cell differentiation. Finally, we determined whether transcript isoforms yielded stable, nuclear targeted proteins that properly bound β-catenin. Materials and Methods

TCF7L2 genetic variants and progression to diabetes in the Chinese population: pleiotropic effects on insulin secretion and insulin resistance

TCF7L2 genetic variants were associated with progression to type 2 diabetes in Europeans. However, the role of TCF7L2 in type 2 diabetes remained uncertain in Chinese. Seventeen tag single nucleotide polymorphisms were genotyped in 1,094 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study. At baseline, the rs7903146 T allele in the exon 4 linkage disequilibrium (LD) block were associated with lower insulinogenic index at 60 min (P = 0.01), while the rs290481 G allele near the 3' end was associated with higher 2-h post-challenge glucose (P = 0.003) and insulin concentration (P = 0.02), elevated systolic (P = 0.01) and diastolic blood pressure (P = 0.006), lower waist circumference (P = 0.01), and increased steady-state plasma glucose (SSPG) concentration measured with modified insulin suppression test (P = 0.02). Over an average follow-up period of 5.43 years, participants with the rs7903146 T allele or variants in the same LD block, but not those with the rs290481 G allele, were more likely to progress to diabetes (hazard ratio = 2.61, 95% confidence interval, 1.27-5.39, P = 0.009) than were non-carriers. TCF7L2 gene expression was inversely associated with SSPG in human visceral (r = -0.73, P = 0.006) and subcutaneous adipose tissue (r = -0.62, P = 0.03). TCF7L2 may exert pleiotropic effects on insulin secretion or insulin resistance. However, only variants associated with impaired beta-cell function predict progression to diabetes in Chinese.

Translating TCF7L2: from gene to function

We are living through a revolution in genetics research. At present, barely a week goes by without a flurry of reports revealing robustly replicated loci associating with a common complex disease. Diabetes was one of the first disease areas to yield results from these genome-wide association studies. Prior to 2006, only two genes were established type 2 diabetes loci (PPARG [1] and KCNJ11 [2]). With the latest round of metaanalyses there are 18 such loci [3, 4], probably more by the time this article goes to print. Themajority of these new loci are in gene regions that were not previously candidates for diabetes. Thus, unravelling these new pathways could potentially reveal new disease mechanisms and new therapies. However, herein lies the difficulty. In this commentary the genetic discovery of TCF7L2 is used as a case study to highlight the challenges that lie ahead in terms of defining the functional and therapeutic impact of diabetes susceptibility genes. Polymorphisms in TCF7L2 that are strongly associated with diabetes risk were identified under an area of linkage on chromosome 10 by the deCODE investigators, who are based in Iceland [5]. This association has since been replicated across multiple ethnic groups, and with a perallele relative risk of 1.4, is the strongest association among the common type 2 diabetes genes [3]. The protein product of TCF7L2 (transcription factor 7-like 2, also referred to as transcription factor 4 or TCF4) is a transcription factor that is involved in the WNT signalling pathway. Importantly, at the time of the deCODE discovery, the role of TCF7L2 in the regulation of the glucagon gene (GCG), which encodes glucagon-like peptide 1 (GLP1) in the gut L cells, had just been described [6]. This immediately implicated TCF7L2 in incretin release or incretin signalling pathways, and an impaired incretin system as the mechanism whereby TCF7L2 polymorphisms increase diabetes risk. However, whilst to some extent supporting this initial hypothesis, studies to determine the mechanism whereby TCF7L2 is implicated in diabetes remains far from clear, as is highlighted in the text box.