Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Polymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study. Ramos RB 2013 et al. OBJECTIVE To assess whether TCF7L2 single nucleotide polymorphisms rs7903146 C/T and rs11196236 C/T are associated with polycystic ovary syndrome (PCOS) in South Brazilian women. DESIGN Cross-sectional study. METHODS 200 PCOS patients and 102 non-hirsute, ovulatory controls were genotyped by real-time polymerase-chain reaction. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using the PHASE 2.1.1 software. RESULTS AND CONCLUSIONS The distribution of rs7903146 (PCOS, 54.4% CC; 28.5% CT; 17.1% TT; controls, 51.0% CC; 37.0% CT; 12.0% TT) and rs11196236 (PCOS, 4.3% CC; 33.5% CT; 62.2% TT; controls, 3.2% CC; 35.5% CT; 61.3% TT) was similar between the groups. rs7903146 and rs11196236 were not in linkage disequilibrium (|D?|=0.34; r2=0.07). PCOS participants were younger, with higher age-adjusted BMI, waist circumference, blood pressure, triglycerides, insulin, HOMA-IR and total testosterone, and lower HDL-c and SHBG vs. controls. In PCOS, no differences between genotypes and haplotypes were found for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dL in total cholesterol (P trend=0.03), and 10.3 mg/dL in LDL-c (P trend=0.01) was recorded. TCF7L2 variants are probably not implicated in PCOS development in South Brazilian women. ///////////////////////// Evidence for Association between Polycystic Ovary Syndrome (PCOS) and TCF7L2 and Glucose Intolerance in Women with PCOS and TCF7L2. Biyasheva A et al. Context and Objective: Of the recently identified T2D susceptibility loci, TCF7L2 confers the greatest relative risk for T2D and significantly predicts conversion to T2D in persons with impaired glucose tolerance. TCF7L2 is, therefore, also a strong candidate gene for polycystic ovary syndrome (PCOS), a common endocrine disorder characterized by androgen excess and menstrual irregularities and associated with insulin resistance and a seven-fold increased risk for T2D. Research Design and Methods: We tested for association between 58 single nucleotide polymorphisms (SNPs) mapping to TCF7L2 and PCOS in 624 index (PCOS) cases and 553 control women of European ancestry. Furthermore, in the women with PCOS, we tested for association with seven reproductive and metabolic quantitative traits. Results: While we did not detect evidence for association between the previously described TCF7L2 T2D locus, the proinsulin:insulin molar ratio, a marker of pancreatic beta-cell dysfunction, was strongly associated with this locus (p=2.1x10(-4)). We also observed evidence for association between PCOS and two SNPs, rs11196236 (p-value=9.0x10(-4)) and rs11196229 (p-value=0.0027) mapping > 100 kb centromeric to the previously published T2D susceptibility loci. Conclusions: We have observed evidence of association with two independent TCF7L2 loci in a PCOS cohort; 1) association between the proinsulin:insulin molar ratio and the T2D locus and 2) association with reproductive PCOS phenotype and a novel locus. This study suggests that variation in different regions of a susceptibility gene contributes to distinct phenotypes.

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Polymorphisms of Transcription Factor-7-Like 2 (TCF7L2) gene in Tunisian women with polycystic ovaries syndrome (PCOS). Ben-Salem A 2013 et al. Background and Aims Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in their child-bearing age, and is often associated with insulin resistance and type 2 diabetes (T2DM). Given the overlap between PCOS and T2DM, we investigated the association of Transcription Factor 7-Like 2 (TCF7L2) variants rs4506565, rs7903146, rs12243326, and rs12255372 with the susceptibility to PCOS Subjects and Methods Study subjects comprised 119 Tunisian women with PCOS (mean age 29.8?4.7years), and 150 control women (mean age 30.6?5.9years). TCF7L2 genotyping was done by the allelic discrimination/real-time PCR method. RESULTS Minor allele frequencies (MAF) of rs4506565 (P=0.61), rs7903146 (P=0.68), rs12243326 (P=0.56), and rs12255372 (P =0.60), were comparable between PCOS cases and controls subjects. As the four tested TCF7L2 variants were in linkage disequilibrium, 4-locus (rs4506565, rs7903146, rs12243326, rs12255372) haplotype analysis demonstrated that haplotype 2111 was initially negatively associated with PCOS P=0.035; OR (95% CI)=0.13 (0.02 - 0.85), which was later lost upon correcting for multiple comparisons Pc=0.248. CONCLUSION Our data suggest that there is weak or no contribution of TCF7L2 gene polymorphism to PCOS in Tunisian women. Further studies with larger samples are necessary to confirm this observation. ///////////////////////// Genetic variants of cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 and transcription factor 7-like 2 are not associated with polycystic ovary syndrome in Chinese women. Liu X et al. Polycystic ovary syndrome (PCOS) is a common disorder in women that shares many genetic features with type 2 diabetes mellitus. Novel risk loci for type 2 diabetes, single nucleotide polymorphism (SNP) rs7756992 in cyclin-dependent kinase 5 (CDK5) regulatory subunit associated protein 1-like 1 (CDKAL1), rs290487 and rs11196218 in transcription factor 7-like 2 (TCF7L2), were recently identified. The aim of this study was to test whether these loci are also associated with PCOS. We recruited 826 patients with PCOS and 620 healthy controls for case-control analysis. The genotypes of these three SNPs were identified. The relationships between PCOS-related clinical endocrine and metabolic features and genotypes were also analyzed. Genotype distribution of these three loci in case and control groups showed no deviation from the Hardy-Weinberg equilibrium. No significant differences in genotype and allele frequencies were found between patients with PCOS and healthy controls. No associations were observed between genotypes of the three SNPs and the clinical endocrine and metabolic features of patients with PCOS in case group after adjustment for body mass index. We concluded that rs7756992 in CDKAL1, rs290487 and rs11196218 in TCF7L2 have no associations with PCOS or PCOS-related clinical features.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Association of Fibrillin-3 and Transcription Factor-7-Like 2 Gene Variants With Metabolic Phenotypes in PCOS. Yalamanchi SK et al. Polycystic ovary syndrome (PCOS) is a complex genetic disease characterized by heritable reproductive and metabolic abnormalities. Genetic variants associated with the reproductive phenotype have been mapped to the fibrillin-3 (FBN3) gene and to a novel transcription factor-7-like 2 (TCF7L2) locus (rs11196236 G). The association of these genetic variants with metabolic phenotypes was investigated in 31 PCOS and 18 control women of European ancestry. The insulinogenic index during an oral glucose tolerance test (?I30/?G30) and insulin secretion rates at the maximal dose during a graded-glucose infusion (ISRmax) were used as indexes of insulin secretion. Endogenous glucose production (EGP) and insulin sensitivity (M/I) were determined during a euglycemic clamp. The disposition index (DI) was calculated using M/I and ?I30/?G30 or ISRmax. Compared with noncarriers (n = 10) and control (n = 10), M/I was decreased (P = 1.1 ?10(-5)) in heterozygous and homozygous PCOS carriers (n = 14) of rs11196236 G and this variant predicted M/I (partial r(2) = 0.34, P = 0.005) in a regression analysis. Postabsorptive EGP tended to be higher (P = 0.040) in heterozygous and homozygous PCOS carriers of the FBN3-associated allele (n = 12), allele 8 of D19S884 (FBN3(+)), compared to PCOS noncarriers (n = 19). PCOS carriers of the rs12255372 T (TCF7L2 Caucasian type 2 diabetes mellitus (T2D) locus) had no significant associated metabolic phenotypes. We conclude that rs11196236 G TCF7L2 variant is associated with peripheral insulin resistance in PCOS but this effect is not seen in control women. The FBN3 risk allele may be associated with changes in basal glucose homeostasis in PCOS. These findings require replication in additional PCOS cohorts.Common variants of transcription factor 7-like 2 (TCF7L2) are associated with reduced insulin secretion in women with polycystic ovary syndrome. Liu B et al. Common variants of the transcription factor 7-like 2 (TCF7L2) gene were identified as one of the few genetic polymorphisms with powerful effects on the risk of type 2 diabetes (T2D). Given the genetic overlap between polycystic ovary syndrome (PCOS) and T2D, the present study was undertaken to investigate whether the TCF7L2 variants are also associated with PCOS. We analyzed single nucleotide polymorphisms (SNPs) rs11196218 and rs290487 of the TCF7L2 gene, which showed robust associations with T2D in Chinese population, in 430 PCOS patients and 360 control subjects by pyrosequencing, and also assessed the effect of genotype on clinical and biochemical traits in the PCOS group. We found no evidence for association between SNP rs11196218 and PCOS. The SNP rs290487 showed marginal differences in genotype frequencies between the PCOS and control group, with the minor C allele being the at-risk allele for PCOS. In PCOS women, the C allele carriers of rs290487 had higher levels of 2h blood glucose but lower insulinogenic index than noncarriers, suggesting impaired insulin secretion. Our data suggested that the TCF7L2 variants may confer an increased risk for early impairment of glucose homeostasis in PCOS.

Species: mouse
Mutation name: None
type: null mutation
fertility: embryonic lethal
Comment: Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Korinek V 1998 et al. Mutations of the genes encoding APC or beta-catenin in colon carcinoma induce the constitutive formation of nuclear beta-catenin/Tcf-4 complexes, resulting in activated transcription of Tcf target genes. To study the physiological role of Tcf-4 (which is encoded by the Tcf7/2 gene), we disrupted Tcf7/2 by homologous recombination. Tcf7/2-/- mice die shortly after birth. A single histopathological abnormality was observed. An apparently normal transition of intestinal endoderm into epithelium occurred at approximately embryonic day (E) 14.5. However, no proliferative compartments were maintained in the prospective crypt regions between the villi. As a consequence, the neonatal epithelium was composed entirely of differentiated, non-dividing villus cells. We conclude that the genetic program controlled by Tcf-4 maintains the crypt stem cells of the small intestine. The constitutive activity of Tcf-4 in APC-deficient human epithelial cells may contribute to their malignant transformation by maintaining stem-cell characteristics. /////////////////////////

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Relationships Between TCF7L2 Genetic Polymorphisms and Polycystic Ovary Syndrome Risk: A Meta-Analysis. Shen WJ 2014 et al. Abstract Objective: This meta-analysis was performed to evaluate the relationships between genetic polymorphisms in the TCF7L2 gene and polycystic ovary syndrome (PCOS) risk. Methods: The PubMed, Centralised Information Service for Complementary Medicine (CISCOM), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Google Scholar, EBSCO, Cochrane Library, and Common Biorepository Model (CBM) databases were searched for relevant articles published before November 1st, 2013, without language restrictions. Meta-analysis was conducted using the STATA 12.0 software. The relationships were evaluated by calculating the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). Seven case-control studies with a total 2458 PCOS patients and 5109 healthy subjects' met our inclusion criteria for qualitative data analysis. Two common polymorphisms (rs7903146 C?T and rs12255372 G?T) in the TCF7L2 gene were assessed. Results: The results of our meta-analysis suggested that TCF7L2 genetic polymorphisms might be strongly correlated with an increased risk of PCOS (allele model, OR=1.33, 95% CI=1.15-1.54, P<0.001; dominant model, OR=1.40, 95% CI=1.12-1.75, P=0.003), especially for the rs7903146 C?T polymorphism. A subgroup analysis was done to investigate the effect of ethnicity on an individual's risk of PCOS. Our results revealed positive significant correlations between TCF7L2 genetic polymorphisms and an increased risk of PCOS among Caucasians (allele model, OR=1.26, 95% CI=1.08-1.47, P=0.004; dominant model, OR=1.33, 95% CI=1.00-1.76, P=0.046) and Asians (allele model, OR=2.02, 95% CI=1.42-2.89, P<0.001; dominant model, OR=2.02, 95% CI=1.40-2.92, P<0.001), but not among Africans (all P<0.05). Conclusions: Our findings provide convincing evidence that TCF7L2 genetic polymorphisms may contribute to susceptibility to PCOS, especially for the rs7903146 C?T polymorphism among Caucasians and Asians. /////////////////////////

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Genetic Polymorphisms of TCF7L2 Lack Influence on Risk of the Polycystic Ovary Syndrome - a Systemic Analysis. Lin L 2014 et al. Background: The results of previous researches that analyzed the association between genetic polymorphisms of transcription factor-7-like 2 (TCF7L2, rs7903146) and polycystic ovary syndrome (PCOS) were conflicting. Current systematic analysis was conducted to re-explore this association using updated materials. Materials and Methods: The PubMed database was used for data collection and the final search was conducted on January 3, 2014. For TCF7L2 rs7903146, a non-signficiant slight increase in risk of PCOS development was observed under three genetic models (dominant model: OR=1.06, 95%CI: 0.93-1.21, p>0.05; recessive model: OR=1.12, 95%CI: 0.87-1.43, p> 0.05; homozygous model: OR=1.14, 95%CI: 0.87-1.47, p>0.05). In the subgroup analyses in Asian group, allele susceptibility of PCOS was calculated (allele model: OR=1.00, 95%CI: 0.74-1.35, p>0.05; dominant model: OR=0.98, 95%CI: 0.71-1.35, p>0.05; recessive model: OR=1.79, 95%CI: 0.33-9.84, p>0.05; homozygous model: OR=1.78, 95%CI: 0.32-9.80, p>0.05), the differences were again not statistically significant. Conclusions: The findings of this systemic analysis suggest that the polymorphism of TCF7L2 rs7903146 may not be associated with the susceptibility to PCOS. /////////////////////////