Transcription Factor 7-like 2 Research Articles

Are single nucleotide polymorphisms rs7903146 and rs12255372 in transcription factor 7-like 2 gene associated with an increased risk for gestational diabetes mellitus in Egyptian women?

BackgroundGenetic variants in the transcription factor 7-like 2 (TCF7L2) gene are related with type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) in various populations, but there are not enough statistics regarding GDM among Egyptian women. We aimed by this study to evaluate the effect of two polymorphisms of rs7903146 and rs12255372 in the TCF7L2 gene with the development of GDM among Egyptian women. ResultsWe enrolled 114 pregnant women with normal glucose tolerance and 114 with GDM according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) guidelines. We gathered records on blood pressure, body mass index (BMI), blood glucose level, hemoglobin A1C (HbA1c), and lipid profile. The genotyping of rs7903146 and rs12255372 polymorphisms was carried out using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The statistical significance of prepregnancy BMI, fasting blood sugar (FBS), HbA1c, low-density lipoprotein (LDL), and total cholesterol (Tch) was higher, P < 0.001, in GDM women in comparison to pregnant women without GDM. CT and TT genotypes in rs7903146 SNP were 46.5% vs. 54%, P <0.04, OR; CI = 1.9 (1.0 to 3.78); TT carriers were 37.7% vs. 9.6%, P <0.001, OR (CI) = 8.9 (3.7–21.1), respectively. For the TCFL2 gene rs12255372 SNP, GT carriers were 48.2% vs. 39.5%, P= 0.004, OR (CI) = 2.3 (1.3–4.2), while TT carriers were 24.6% vs. 7.9%, P < 0.001, OR (CI) = 6 (2.5–14.3). ConclusionThe study showed there is a significantly higher incidence of CT/TT genotypes in rs7903146 SNP and GT/TT genotypes in rs12255372 SNP in TCF7L2 gene among GDM women in comparison to healthy pregnant women (controls).

Transcription Factor 7-Like-2 (TCF7L2) rs7903146 (C/T) Polymorphism in Patients with Type 2 Diabetes Mellitus

Abstract Background Type 2 diabetes mellitus (T2DM) is a heterogeneous group of metabolic disorders characterized by the incapability of pancreatic beta cells to increase insulin secretion to compensate for insulin resistance in the peripheral tissues. T2DM is a multi-factorial disease including several environmental factors with the presence of genetic predisposition. The transcription factor 7-like-2 gene (TCF7L2) rs7903146 (C/T) polymorphism is one of the most susceptible genes to T2DM discovered to date, with contribution to the disease through the Wnt/β –catenin signaling pathway affecting pancreatic islet development, expression of several genes involved in insulin granules exocytosis and the incretin glucagon-like peptide 1 (GLP-1) gene. Aim of the Work In this study we aimed to investigate the potential association of the transcription factor 7-like-2 (TCF7L2) rs7903146 (C/T) gene polymorphism in patients with type 2 diabetes mellitus. Patients and Methods The study was a case- control study conducted on 70 T2DM patients recruited from the endocrinology clinic at Ain Shams University Hospitals, and 30 non diabetic healthy controls matched with the patients in age and sex. All subjects underwent full history taking, thorough clinical examination, routine laboratory investigations including haemoglobin A1c (HbA1c), lipid profile; total cholesterol (TC), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C) and determination of TCF7L2 gene polymorphism by real-time quantitative polymerase chain reaction (RT-PCR). Results The minor T allele of the rs7903146(C/T) SNP was associated with high risk of development of T2DM with an OR of 1.35 (95% CI: 0.68-2.6), the heterozygous genotype (CT) with an OR 1.16 (95% CI: 0.49-2.7) and the homozygous mutant genotype (TT) with OR of 3.16 (95% CI: 0.15-6.31), however, they were statistically insignificant (p-value &amp;gt;0.05). Conclusion Our study did not confirm the presence of significant association between the TCF7L2 rs7903146(C/T) polymorphism and T2DM, however, it pointed to the possibility of presence of high risk of development of T2DM in patients with TT genotype. Further studies with higher sample size are needed to clarify the association.

TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling

Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

Transcription Factor-7-Like-2 (TCF7L2) in Atherosclerosis: A Potential Biomarker and Therapeutic Target.

Transcription factor-7-like-2 (TCF7L2), a vital member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family, plays an important role in normal human physiological and pathological processes. TCF7L2 exhibits multiple anti-atherosclerotic effects through the activation of specific molecular mechanisms, including regulation of metabolic homeostasis, macrophage polarization, and neointimal hyperplasia. A single-nucleotide substitution of TCF7L2, rs7903146, is a genetic high-risk factor for type 2 diabetes and indicates susceptibility to cardiovascular disease as a link between metabolic disorders and atherosclerosis. In this review, we summarize the anti-atherosclerosis effect and novel mechanisms underlying the function of TCF7L2 to elucidate its potential as an anti-atherosclerosis biomarker and provide a novel therapeutic target for cardiovascular diseases.

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.

Transcription factor 7-like 2 gene- smoking interaction on the risk of diabetic nephropathy in Chinese Han population

ObjectivesTo evaluate the relationship between transcription factor 7-like 2 (TCF7L2) gene polymorphism and diabetic nephropathy (DN) risk, as well as the effect of gene-environment interactions on DN risk in Chinese Han population.MethodsThe Hardy-Weinberg equilibrium (HWE) and the relationship between TCF7L2 gene single nucleotide polymorphism (SNPs) and DN susceptibility were evaluated by SNPStats. The interaction among four SNPs and environmental factors were tested by generalized multifactor dimensionality reduction (GMDR). The consistency of cross validation, accuracy of test balance and sign test were calculated to evaluate the interaction of each selection. The logistic regression was used to test the interaction between rs7903146 and current smoking by stratified analysis.ResultsLogistic regression analysis indicated that the DN risk of rs7903146-T allele carriers were obviously higher than that in CC genotype carriers (CT + TT versus CC), adjusted OR (95 %CI) = 1.64 (1.24–2.06). However, we also discovered that people with rs12255372, rs11196205 and rs290487 minor allele had non-significant difference risk of DN compared with people with major allele. The GMDR model found a significant two-locus model (p = 0.0100) including rs7903146 and current smoking, suggesting a potential gene–environment interaction between rs7903146 and current smoking. Compared with never smokers with rs7903146- CC genotype, current smokers with rs7903146- CT or TT genotype had the highest DN risk. After covariate adjustment, OR (95 %CI) was 2.15 (1.58–2.78).ConclusionsWe found a significant relationship of rs7903146-T alleles, and the interaction between rs7903146-T and current smoking with increased DN risk.

Dietary Macronutrient Intake May Influence the Effects of TCF7L2 rs7901695 Genetic Variants on Glucose Homeostasis and Obesity-Related Parameters: A Cross-Sectional Population-Based Study.

Transcription factor-7–like 2 (TCF7L2) is one of the most important susceptibility genes for type 2 diabetes mellitus (T2DM). The aim of our cross-sectional population-based study was to analyze whether daily macronutrient intake may influence the effects of the TCF7L2 rs7901695 genotype on glucose homeostasis and obesity-related parameters. We recruited 810 participants (47.5% men and 52.5% women), 18–79 years old (mean age, 42.1 (±14.5) years), who were genotyped for the common TCF7L2 rs7901695 single-nucleotide polymorphism (SNP), and anthropometric measurements, body composition, body fat distribution (visceral (VAT) and subcutaneous adipose tissue (SAT) content), blood glucose and insulin concentrations after fasting and during OGTTs, and HbA1c were assessed. The VAT/SAT ratio, HOMA-IR (homeostatic model assessment of insulin resistance), HOMA-B (homeostatic model assessment of β-cell function), and CIR30 (corrected insulin response) were calculated. The daily macronutrient intake was evaluated based on 3-day food-intake diaries. Daily physical activity was evaluated based on a validated questionnaire. We performed ANOVA or Kruskal–Wallis tests, and multivariate linear regression models were created to evaluate the effects of dietary macronutrient intake on glucose homeostasis and obesity-related parameters in carriers of the investigated genotypes. This study was registered at ClinicalTrials.gov as NCT03792685. The TT-genotype carriers stratified to the upper protein intake quantiles presented higher HbA1c levels than the CT- and CC-genotype participants in the same quantiles (p = 0.038 and p = 0.022, respectively). Moreover, we observed higher HOMA-IR (p = 0.014), as well as significantly higher blood glucose and insulin concentrations, during the OGTTs for those in the upper quantiles, when compared to subjects from the lower quantiles of protein intake, while the CC-genotype carriers presented significantly lower HbA1c (p = 0.033) and significantly higher CIR30 (p = 0.03). The linear regression models revealed that an increase in energy derived from proteins in TT carriers was associated with higher HbA1c levels (β = 0.37 (95% CI: 0.01–0.74, p = 0.05)), although, in general, carrying the TT genotype, but without considering protein intake, showed an opposite tendency—to lower HbA1c levels (β = −0.22 (95% CI: 0.47 to −0.01, p = 0.05). Among the subjects stratified to the lower quantile of carbohydrate intake, the TT-genotype individuals presented higher HbA1c (p = 0.041), and the CC-genotype subjects presented higher VAT (p = 0.033), lower SAT (p = 0.033), and higher VAT/SAT ratios (p = 0.034). In both the CC- and TT-genotype carriers, we noted higher VAT (p = 0.012 and p = 0.0006, respectively), lower SAT (p = 0.012 and p = 0.0006, respectively) and higher VAT/SAT ratios (p = 0.016 and p = 0.00062, respectively) when dietary fat provided more than 30% of total daily energy intake, without any differences in total body fat content. Our findings suggest that associations of the common TCF7L2 SNP with glucose homeostasis and obesity-related parameters may be dependent on daily macronutrient intake, which warrants further investigations in a larger population, as well as interventional studies.

Association of TCF7L2 rs7903146 Polymorphism with Diabetic Nephropathy in Type 2 Diabe-tes Mellitus Egyptian Patients

Background: Transcription factor 7-like 2 (TCF7L2) gene polymorphisms are known risk factors for type 2 diabetes mellitus (T2DM). However, the relationship between TCF7L2 polymorphism and diabetic nephropathy (DN) is inconclusive. Objectives: to explore the association of TCF7L2 rs7903146 (C/T) gene polymorphism and DN in T2DM Egyptian patients. Methods: 80 patients with T2DM (40 patients without DN and 40 patients with DN) were enrolled in the study. Genotyping for the rs7903146 (C/T) polymorphism in TCF7L2 gene was performed by real time PCR. Results: The frequency of rs7903146 genotypes in diabetic patients without DN was ( CC: 57.5%; CT: 37.5%; TT: 5%), while in diabetic patients with DN was (CC: 2.5%; CT: 40%; TT: 57.5%). Patients with DN were exposed to the TT 25.7 times more than who didn’t develop DN (OR= 25.7, 95% CI= 0.43-94, P= 0.001**). Upon examining the allelic discrimination, C allele was present in 77.5% of patients without DN versus 23.8% of patients with DN, While T allele was found in 22.5% of patients without DN versus 76.3% of patients with DN. Patients with DN were exposed to the T allele 11 times more than who didn’t develop nephropathy (OR=11, 95% CI= 5.3-23.1 , P=<0.001**). Conclusion: rs7903146 TCF7L2 gene polymorphism may be significantly associated with the susceptibility to DN in Egyptian T2DM patients.

TCF7L2 gene polymorphism as a risk for type 2 diabetes mellitus and diabetic microvascular complications

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition with various genetics and environmental influences that affects the capacity of the body to produce or use insulin resulting in hyperglycemia, whichmayleadtovariablecomplications. It is one of the world'srisinghealth problems. Thereisemerging evidence that some genetic polymorphisms can impact the risk of evolving T2DM. Wetrytodeterminetherelationship of (rs7903146) variant of the Transcription factor 7-like 2 (TCF7L2) gene with T2DM and its microvascular complications. This case-control study included 180 subjects: 60 diabetic patients without complications, 60 diabetic patients with microvascular complications and 60 matched healthy controls. Genotypes of rs7903146 (C/T) SNP in the TCF7L2 gene were evaluated by real-time polymerase chain reaction via TaqMan allelic discrimination. Logistic regression was used to detect the most independent factor for development of diabetes and diabetic microvascular complications. Variant homozygous TT and heterozygous CT genotypes were significantly increased in diabetic without complications and diabetic with complications groups than controls (p = 0.003, 0.001) respectively. The T allele was more represented in both patient groups than controls with no significant difference between patient groups. TT genotype as well as T allele was significantly associated with increased T2DM risk. The T allele of rs7903146 polymorphism of TCF7L2 confers susceptibility to development of T2DM. However, no significant association was found for diabetic complications.

Associations of TCF7L2 rs11196218 (A/G) and GLP-1R rs761386 (C/T) Gene Polymorphisms with Obesity in Chinese Population.

IntroductionThis study aimed to investigate the genetic polymorphism associations with obesity of the transcription factor 7-like 2 (TCF7L2) gene rs11196218 (A/G) and glucagon-like peptide 1 receptor (GLP1-R) gene rs761386 (C/T) in the Chinese population.Patients and MethodsThis was a case–control pilot study involving 60 patients with obesity and 69 non-obesity Chinese adults, and the two groups were sex and age matched. Anthropometric indices of obesity, fasting blood glucose, blood pressure, and blood lipids were assessed. Both polymorphisms were genotyped using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF).ResultsThere were significant differences in the allelic frequencies of the TCF7L2 rs11196218 and GLP1-R rs761386 between obesity and non-obesity groups (P = 0.003, OR = 2.32, 95% CI [1.31~4.09]; P = 0.034, OR = 1.94, 95% CI [1.05~3.60], respectively). In allele model, the genotypic frequencies of TCF7L2 rs11196218 and GLP1-R rs761386 also differed between obesity and non-obesity groups (P = 0.014 and 0.033, respectively). In dominant model, the TCF7L2 rs11196218 A-carrier (AA/AG) had a higher risk of obesity than GG genotype (P = 0.014, OR = 2.54, 95% CI [1.21~5.35]). Comparison of clinical and biochemical parameters between genotypes showed no significant difference.ConclusionThese findings suggest that the rs11196218 (A/G) polymorphism of the TCF7L2 gene and the rs761386 (C/T) polymorphism of the GLP1-R gene were associated with obesity in the Chinese population.

Interaction between TCF7L2 rs7903146 Genotype, HbA1c Levels, and the Periodontal Status of Dental Patients.

Objective The aim of the study was to investigate the potential interaction between TCF7L2 rs7903146 genotype, which is implicated for type-2 diabetes mellitus genetic susceptibility, HbA1c levels, and the periodontal status of dental patients. Materials and Methods HbA1c levels, clinical periodontal parameters (probing depth, clinical attachment level, bleeding on probing, and plaque index), and several parameters (such as body mass index [BMI], smoking habits, education level, and age) were recorded in 150 patients who fulfilled the criteria for screening for prediabetes/diabetes of the Centers for Disease Control and Prevention. DNA was extracted and the TCF7L2 single nucleotide polymorphism (SNP) rs7903146 was genotyped in all participants. Results Thirty-one patients out of 150 tested were found with unknown hyperglycemia (20.7%). Regarding sex, education, parent with diabetes, normal BMI, smoking, age ≥45 years and prior testing for diabetes, no differences were observed between patients displaying HbA1c < 5.7 and ≥ 5.7% (Pearson’s Chi-square test, p > 0.05). Regarding periodontal parameters and differences between subgroups (HbA1c levels ≥ 5.7 and HbA1c levels < 5.7), statistically significant differences were observed for probing depth (3.20 ± 0.94 vs. 2.81 ± 0.78 mm), clinical attachment level (3.54 ± 1.20 vs. 3.18 ± 1.06 mm) and bleeding on probing (0.62 ± 0.25 vs. 0.50 ± 0.24%) with hyperglycemic patients exhibiting worse periodontal conditions (Mann–Whitney test p < 0.05). The allelic and genotype frequencies for the transcription factor 7-like 2 ( TCF7L2 ) gene, SNPs 7903146 did not exhibit a significant difference between the HbA1c > 5.7 and HbA1c < 5.7 groups and the periodontitis and nonperiodontitis subgroups respectively (Fisher’s exact test >0.05). Statistical Analysis Patient characteristics and their association with prediabetes were tested by Pearson’s Chi-square test (asymptotic, two sided). Differences of periodontal parameters between subgroups were tested with the Mann–Whitney U-test. The associations of allele and genotype frequencies in the patient and control groups were analyzed using the Fisher’s exact test of independence.The significance level was set at the 0.05 for all tests. Conclusion A statistically significant association between TCF7L2 rs7903146 genotype and periodontal condition or HbA1c levels was not observed in contrast to statistically significant differences of clinical parameters of periodontitis in patients with hyperglycemia.

Significant Association of Polymorphisms in the TCF7L2 Gene with a Higher Risk of Type 2 Diabetes in a Moroccan Population.

Background and aims: Several studies have shown that genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) are highly associated with the development of type 2 diabetes mellitus (T2DM) and its associated complications in several populations. The aim of our study was to investigate the association of the rs7903146 (C/T) and rs12255372 (G/T) polymorphism in the TCF7L2 gene with the risk of developing T2DM in the Moroccan population. Material and methods: A total of 150 T2DM patients and 100 healthy controls were recruited for various anthropometric, biochemical and genetic parameters. Genotyping was performed by using Real Time-PCR. The frequency of genotypes, alleles, anthropometric measures, glycemia, glycated hemoglobin (HbA1c) were evaluated in patients and control, while lipid profile was available only for T2DM group. Results: Glycemia, HbA1c and body mass index (BMI) were significantly higher in T2DM group than control. Analysis of the distribution of the TCF7L2 rs7903146 genotype and allele revealed that the TT genotype was more frequent in T2DM group (24.0%) than in healthy controls (5%) (OR = 4.08, 95% confidence interval (CI = 1.95–11.80, p < 0.0001). The T allele was more frequent in diabetic patients (45.2%) than healthy control (34.5%) and it was associated with high risk of diabetes (OR = 2.13, 95% CI = 1.12–7.31, p = 0.005). The same results were found regarding rs12255372, TT genotype frequencies were 18,7% and 6.0% in T2DM and control group, respectively (OR = 3.11, 95% CI = 1.33–7.24, p = 0.004). The T allele was over-presented in diabetics compared to controls (45.3% and 38.0%, respectively) and increases the risk of T2DM (OR = 2.01, 95% CI = 1.04–3.10, p = 0.01). However, there was no significant difference between the three genotypes of rs7903146 and rs12255372 regarding age, BMI, glycemia, HbA1c and lipid profile. Conclusion: The present study confirmed a significant association of the TCF7L2 gene (rs7903146 (C/T) and rs12255372 (G/T) polymorphisms with a higher risk to T2DM in the Moroccan population. No significant difference in respect to anthropometric and metabolic parameters between different genotypes.

Lack of association between single nucleotide polymorphisms in TCF7L2 and T2DM in the Chinese Yao population: A case-control study.

Single-nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 (TCF7L2) gene have been identified to be associated with the susceptibility to type 2 diabetes mellitus (T2DM) in various populations worldwide, but the results in Chinese are conflicting, and no data are available about the Liannan Yao population. Therefore, this study aimed to investigate the association of the TCF7L2 gene polymorphisms (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) with T2DM in the Yao population living in the rural areas in the Liannan Yao Autonomous County.This was a case-control study of 28 subjects with T2DM or prediabetes and 52 non-T2DM controls, all from the Chinese Yao population and recruited between January 2019 and June 2020. Patients with T2DM and prediabetes were grouped as the case group. The five SNPs (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) were examined by polymerase chain reaction and direct genomic DNA sequencing in case and control groups.The subjects in case group were older than the controls (55±14 vs 48 ± 15 years, P = .047), had higher FBG levels (9.31 ± 5.43 vs 4.09 ± 0.81, P < .001), higher TC (5.79 ± 1.29 vs 5.13 ± 1.18 mmol/L, P = .025), and higher triglycerides (2.94 ± 2.04 vs 1.86 ± 1.39 mmol/L, P = .003). The genotypic distribution for each of the SNPs was in agreement with the Hardy-Weinberg equilibrium. There were no statistically significant differences in the distributions of genotypes or alleles at all five SNPs of the TCF7L2 gene between the case and control groups (all P > .05).TCF7L2 SNPs were not associated with T2DM in the Liannan Yao population.

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.

Associations of transcription factor 7-Like 2 (TCF7L2) gene polymorphism in patients of type 2 diabetes mellitus from Khyber Pakhtunkhwa population of Pakistan.

Type 2 diabetes mellitus (T2DM) is the most prevalent component of metabolic syndrome. Environmental factors and various complex genes like transcription factor 7-like 2 (TCF7L2) gene have involved in the disease development. To determine TCF7L2 genetic association (rs7903146C/T and rs12255372G/T) in T2DM patients of Khyber Pakhtunkhwa population of Pakistan. This study comprised of 176 subjects including 118 T2DM patients and 58 healthy controls. Genomic DNA was extracted and genotype of common variants (rs7903146 C/T and rs12255372 G/T) was carried out by amplification-refractory mutation system (ARMS)-PCR of sequence specific oligonucleotides. The distribution of genotype of TCF7L2 SNPs (rs7903146 C/T and rs12255372 G/T) was significantly associated with T2DM as compared to the controls (p <0.0001). The genetic models of the rs7903146 (C/T) and rs12255372 (G/T) SNPs were significantly associated between cases and controls (p <0.0001). On the other hand, the significant association was observed between the two SNPs and different biochemical parameters like serum fasting glucose, lipid profile, creatinine and blood HbA1c levels (p <0.05). It is concluded that the SNPs of the TCF7L2 gene are significantly associated with T2DM disease susceptibility in the population of Khyber Pakhtunkhwa of Pakistan.

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer.

Simple SummaryUnraveling the mechanistic regulations that influence tumor behavior is an important step towards treatment. However, in vitro studies capture only small parts of the complex signaling cascades leading to tumor development. Mechanistic modeling, instead, allows a more holistic view of complex signaling pathways and their crosstalk. These models are able to suggest mechanistic regulations that can be validated by targeted and thus more cost-effective experiments. This article presents a logical model of pancreatic cancer cells with high cofilin-1 expression. The model includes migratory, proliferative, and apoptotic pathways as well as their crosstalk. Based on this model, mechanistic regulations affecting tumor promotion could be unraveled. Moreover, it was applied to screen for new therapeutic targets. The development of resistance mechanisms is a common limitation of cancer therapies. Therefore, new approaches are needed to identify optimal treatments. One is suggested in this article, indicating the surface protein CD44 as a promising target.Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression.

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.

Abstract PO049: Compartment-specific profiling for evaluation of disrupted signaling in early stage, low-grade endometrial cancer

Abstract Understanding tumor microenvironment is critical to improving conservative management (non-surgical) strategies for early stage, low grade endometrial cancer (EC). This remains an unmet clinical need for women who wish to maintain fertility and those who cannot undergo surgery due to medical co-morbidities. Current regimens rely on progestin treatment, but resistance and early relapse require improved therapeutic strategies. We sought to evaluate alterations in gene expression in the epithelial and stromal compartment of EC compared to normal endometrium to identify targets for combination therapies. RNA was extracted from microdissected epithelial and stromal compartments of formalin fixed paraffin embedded early stage, low grade EC and normal endometrium (NE). Comprehensive transcriptome profiling was performed with Affymetrix Clariom D assay and pathway analysis was performed. Immunohistochemistry (IHC) was used for validation. Functional studies of differentially expressed genes were performed in Hec1A EC cell lines. Among differentially expressed genes in EC vs NE, multiple altered signaling pathways were identified. EIF2 signaling, eIF4 and p70S6K signaling, and PI3K/AKT/mTOR were the most significant pathways activated in both epithelial and stromal compartments. In the epithelia compartment, the most significant gene expression changes included reduced expression of RBPMS (RNA Binding Protein with Multiple Splicing), SORD (Sorbitol Dehydrogenase), DDX17 (DEAD-Box Helicase 17), and TPT1 (Translationally-Controlled Tumor Protein) in EC, while MTDH (Metadherin) was significantly increased in EC. Similar changes were observed in the stroma compartment, but with lower fold changes than that observed in gland. Together with decreased RBPMS expression, decreased RBPMS-interacting molecules IGF2, TCF7L2 (Transcription Factor 7 Like 2), FOS (Proto-Oncogene C-Fos) and increased GPS2 (G protein Pathway Suppressor 2) were also observed. Differential expression of proteins in gland and stroma was also confirmed by IHC. An inverse correlation of RBPMS expression and EC proliferation was also observed in EC at the protein level. Enhanced AKT and S6 protein phosphorylation were observed by RBPMS silencing in Hec1A endometrial cells. Reverse Phase Protein Array demonstrated activation of Caveolin 1, FOXO3 (Forkhead Box O3), MT-CO1 (Mitochondrially Encoded Cytochrome C Oxidase I), L1CAM (L1 Cell Adhesion Molecule) with RBPMS silencing in Hec1A cell. These molecules are involved in pathways such as molecular mechanisms of cancer, estrogen receptor signaling, and senescence pathway. While estrogen-regulated changes were prominent in early stage low-grade EC, the identification of additional signaling changes provide support for an ongoing trial of levonorgestrel IUD + everolimus (mTOR inhibitor) and can be probed further to identify new targets for combination conservative management strategies. Additionally, biomarkers from these pathways, such as RBPMS, can be studied to guide the selection of progestin-only therapy versus combination therapy. Citation Format: Qian Zhang, Xiaoping Su, Joseph Celestino, Ying Yuan, Samuel C. Mok, Karen H. Lu, Melinda S. Yates. Compartment-specific profiling for evaluation of disrupted signaling in early stage, low-grade endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO049.

Transcription factor 7-like 2 (TCF7L2) rs12255372 variant and the risk of type 2 diabetes mellitus among the Kurdish population in Erbil, Iraq

The genetic predispositions related to type 2 diabetes (T2D) in the Middle East are poorly understood. One of the most common single-nucleotide polymorphisms (SNP) located in the transcription factor 7-like-2 (TCF7L2) gene is rs12255372 variant which elucidated a significant role in developing T2D, especially in the European population. The current study is the first to have examined the association between TCF7L2 rs12255372 variant and T2D among the Iraqi Kurdish population from Iraq. Three hundred participants were enrolled in this study: 150 were type 2 diabetic patients and 150 were normoglycemic controls. For genotyping rs12255372 (G > T) variant, Tetra ARMS-PCR was used which is high-throughput, cost and time effective technique. The genotypic frequencies in the additive genetic model (co-dominant) for GG, GT, and TT were 62.7%, 24%, and 13.3% in the normoglycemic controls, respectively, and for the diabetic patients were 50.7%, 20%, and 29.3%, respectively. The TT genotype was found considerably higher in cases when matched to the normoglycemic controls in both co-dominant and recessive models with OR (95% CI) = 2.64 (1.29–5.41) (p value = 0.006) and OR (95% CI) = 1.531 (1.232–1.902) (p value = 0.001), respectively. These frequencies indicated that the carriers of the TT genotype were more susceptible to T2D compared to other genotypes. The T allele showed a high significant frequency in T2D patients compared to the normoglycemic controls with OR (95% CI) = 1.38 (1.16–1.59) (p value = 0.000). Our results suggest rs12255372 T allele as a putative risk factor that increases the susceptibility of T2D among the Iraqi Kurdish population.

The Wnt Effector TCF7l2 Promotes Oligodendroglial Differentiation by Repressing Autocrine BMP4-Mediated Signaling.

Promoting oligodendrocyte (OL) differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector transcription factor 7-like 2 (TCF7l2) was upregulated in MS lesions and had been proposed to inhibit OL differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here, we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP)4-mediated signaling. Disrupting TCF7l2 in mice of both sexes results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes OL differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested OL differentiation elicited by TCF7l2 disruption in vivo Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS.SIGNIFICANCE STATEMENT Incomplete or failed myelin repairs, primarily resulting from the arrested differentiation of myelin-forming oligodendrocytes (OLs) from oligodendroglial progenitor cells, is one of the major reasons for neurologic progression in people affected by multiple sclerosis (MS). Using in vitro culture systems and in vivo animal models, this study unraveled a previously unrecognized autocrine regulation of bone morphogenetic protein (BMP)4-mediated signaling by the Wnt effector transcription factor 7-like 2 (TCF7l2). We showed for the first time that TCF7l2 promotes oligodendroglial differentiation by repressing BMP4-mediated activity, which is dysregulated in MS lesions. Our study suggests that elevating TCF7l2 expression may be possible in overcoming arrested oligodendroglial differentiation as observed in MS patients.