Transcription Factor 7-like 2 Research Articles

Silencing of long noncoding RNA MYLK-AS1 suppresses nephroblastoma via down-regulation of CCNE1 through transcription factor TCF7L2.

Nephroblastoma, a pediatric kidney cancer, caused by pluripotent embryonic renal precursors. Long noncoding RNAs (lncRNAs) are commonly abnormal expressed in many cancers. In the present study, we fousced on one newly discrovered lncRNA, MYLK Antisense RNA 1 (MYLK-AS1), and its functional role in proliferation and cycle distribution of nephroblastoma cells. Micorarray-based analysis revealed the highly expressed Cyclin E1 (CCNE1) and MYLK-AS1 in nephroblastoma. After nephroblastoma tissue sample collection, RT-qPCR confirmed the upregulated expression of MYLK-AS1 and CCNE1 in nephroblastoma tissues and cells. Kaplan-Meier curve exhibited that patients with elevated CCNE1 had lower overall survival rate in follow-up study. RNA binding protein immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were employed to determine the relationship among MYLK-AS1, TCF7L2, and CCNE1, which validated that transcription factor 7-like 2 (TCF7L2) could specifically bind to MYLK-AS1 and TCF7L2 could positively promote CCNE1. After gain- and loss-of function assays, the conclusion that silencing of MYLK-AS1 could inhibit expression of CCNE1 through the transcription factor TCF7L2 to regulate the cell proliferation and cell cycle distribution of nephroblastoma cells was obtained. Subsequently, the subcutaneous tumor formation ability of nephroblastoma cell in nude mice was observed and the silencing of MYLK-AS1 exerts suppressive role in the tumorigenic ability of nephroblastoma cells in vivo. Taken together, MYLK-AS1 constitutes a promising biomarker for the early detection and treatment of nephroblastoma.

Heat Shock Protein 70 (HSP70) Protein-Protein Interactions and a Putative Mechanism for the Potential Benefits of Heat Therapy for Type 2 Diabetes Mellitus

The use of heat therapy to treat diseases was very common in Africa. To date, the number of people using this form of therapy is very much on the decrease. Data on the molecular action mechanisms of how it might induce beneficial effects remain unknown. The aim of the present study was to make a contribution towards understanding the putative implication of Heat Shock Protein 70 (HSP70) in the pathophysiology of Type 2 Diabetes Mellitus (T2DM) and the hypothetical benefits of heat therapy through the establishment of a network of protein-protein interactions between Krüppel Like Factor 14 (KLF14), Transcription Factor 7 Like 2 (TCF7L2), Peroxisome Proliferator-Activated Receptor Gamma (PPARG) and HSP70 (HSPA4). Data were generated by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software version 10.0. This was used to identify the known and predicted protein-protein interactions (including direct or physical and indirect or functional associations) in the KLF14, TCF7L2, PPARG and HSP70 protein networks. With the active prediction methods (Gene Fusion, Neighborhood, Co-occurrence, Co-expression, Experiments, Databases and Text Mining) as interaction sources, Medium Confidence (0.400) and maximum number of interactions were used to show no more than 50 at the first shell and none at the second shell parameters. Fifty (50) proteins were identified to interact with these four proteins, namely KLF14, TCF7L2, PPARG and HSP70, resulting in a network diagram with 54 nodes (gene/proteins) and 485 edges, representing protein-protein associations. The network showed that HSP70 strongly interacts with other heat shock proteins like HSP90. The HSPBP, a cytoplasmic co-chaperone 1, inhibits HSPA1A chaperone activity by changing the conformation of its ATP-binding domain, thus interfering with this function. Based on the data generated by this <i>in silico</i> study, the potential beneficial effects of heat therapy on T2DM could probably be coordinated by the HSP70 protein-protein interactions involved in cell life and in the susceptibility to T2DM.

Association of TCF7L2 gene polymorphisms, methylation, and gene-environment interaction with type 2 diabetes mellitus risk: A nested case-control study in the Rural Chinese Cohort Study.

To assess the associations of single-nucleotide polymorphisms (SNPs) and methylation of transcription factor 7-like 2 (TCF7L2) gene with type 2 diabetes mellitus (T2DM) risk and further explore the interactions among SNPs, methylation, and environmental factors involved in T2DM risk. We conducted a nested case-control study with 290 pairs of T2DM cases and matched controls. We genotyped 3 SNPs of TCF7L2 in all included participants and tested 14 CpG loci of TCF7L2 in 76 pairs of cases and controls. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for T2DM risk according to SNPs and methylation of TCF7L2. Multifactor dimensionality reduction (MDR) analysis was used to explore the potential TCF7L2 gene-environment interactions in T2DM risk. We found no statistically significant association between the TCF7L2 polymorphisms and T2DM risk. We observed significant positive associations of methylation at CpG5 and CpG7_8 with T2DM risk. For each 1% increase in DNA methylation at CpG5 and CpG7_8, T2DM risk increased 12% (OR 1.12, 95% CI 1.01-1.25) and 32% (OR 1.32, 95% CI 1.07-1.63), respectively. Additionally, MDR analyses identified significant SNP-environment interactions among rs290487, alcohol drinking, and hypertension and methylation-environment interactions among CpG5, CpG7_8 and hypertension (P <0.05). TCF7L2 polymorphisms were not independently associated with T2DM risk. However, TCF7L2 methylation were positively associated with T2DM risk in rural Chinese adults. Interactions among TCF7L2 polymorphisms, TCF7L2 methylation and environmental factors also suggest a possible etiologic pattern for T2DM.

TCF7L2 rs7903146 C&gt;T gene polymorphism is not associated with hypoglycemia in sulfonylurea-treated type 2 diabetic patients

Abstract Objectives Hypoglycemia is the most common adverse effect of sulfonylureas (SUs) and a major concern when using these drugs. Transcription factor 7-like 2 (TCF7L2) rs7903146 C&gt;T polymorphism is an established and well characterized genetic marker of type 2 diabetes (T2DM) risk. The aim of the present study was to analyze the potential association of TCF7L2 rs7903146 C&gt;T polymorphism with SU-induced hypoglycemia in a well characterized cohort of SU-treated patients previously genotyped for cytochrome P450 2C9 (CYP2C9) and P450 oxidoreductase (POR). Methods The study group consisted of 176 SU-treated T2DM patients of whom 92 had experienced at least one drug-associated hypoglycemic event. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for TCF7L2 rs7903146 genotyping. Results TCF7L2 rs7903146 C&gt;T genotype and allele frequency did not differ between cases and controls (p=0.745 and 0.671, respectively). In logistic regression analysis adjusted for other factors affecting hypoglycemia, including CYP2C9 and POR genotypes, TCF7L2 rs7903146 C&gt;T polymorphism did not increase the risk of hypoglycemia (OR=1.238, 95% C.I.=0.750–2.044, p=0.405). Conclusions TCF7L2 rs7903146 C&gt;T polymorphism is not associated with SU-induced hypoglycemia. Identifying additional gene polymorphisms associated with SU-induced hypoglycemia is crucial for improving T2DM patient therapy with SUs.

Single nucleotide polymorphism rs7908486 of the TCF7L2 gene is highly associated with obesity in the Iraqi population

This study was conducted to assess the possible association between polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and obese Iraqi adults. DNA was obtained from 158 obese subjects and 142 controls. Two specific PCR fragments were designed to incorporate two highly frequent single nucleotide polymorphism (SNP)s within TCF7L2, rs11196208 and rs7908486. Both amplified loci were genotyped by PCR-single-strand conformation polymorphism (SSCP) followed by sequencing. Logistic regression analysis was performed to detect the association between both genetic variants and obesity. Concerning rs11196208-based amplicons, PCR-SSCP genotyping showed homogeneous banding patterns for all investigated samples. In contrast with rs11196208, three SSCP banding patterns in the rs7908486-based amplicons, GG, AG and AA, were observed. Individuals with the AA genotype showed significantly higher (P&lt;0.05) body mass index (BMI), waist circumference (WC), fasting blood glucose (FBG), and insulin values than those with either AG or GG genotypes. Association analysis revealed that individuals with the A allele exhibited a greater risk of obesity than individuals with the B allele. Data indicate that rs7908486 SNP exerted a tight association with obesity. The study suggests implementing TCF7L2 rs7908486-based genotyping in the early detection of obesity.

TCF7L2 rs7903146 C>T gene polymorphism is not associated with hypoglycemia in sulfonylurea-treated type 2 diabetic patients.

Hypoglycemia is the most common adverse effect of sulfonylureas (SUs) and a major concern when using these drugs. Transcription factor 7-like 2 (TCF7L2) rs7903146 C>T polymorphism is an established and well characterized genetic marker of type 2 diabetes (T2DM) risk. The aim of the present study was to analyze the potential association of TCF7L2 rs7903146 C>T polymorphism with SU-induced hypoglycemia in a well characterized cohort of SU-treated patients previously genotyped for cytochrome P450 2C9 (CYP2C9) and P450 oxidoreductase (POR). The study group consisted of 176 SU-treated T2DM patients of whom 92 had experienced at least one drug-associated hypoglycemic event. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for TCF7L2 rs7903146 genotyping. TCF7L2 rs7903146 C>T genotype and allele frequency did not differ between cases and controls (p=0.745 and 0.671, respectively). In logistic regression analysis adjusted for other factors affecting hypoglycemia, including CYP2C9 and POR genotypes, TCF7L2 rs7903146 C>T polymorphism did not increase the risk of hypoglycemia (OR=1.238, 95% C.I.=0.750-2.044, p=0.405). TCF7L2 rs7903146 C>T polymorphism is not associated with SU-induced hypoglycemia. Identifying additional gene polymorphisms associated with SU-induced hypoglycemia is crucial for improving T2DM patient therapy with SUs.

Genetic variants of TCF7L2 gene and its coherence with metabolic parameters in Lithuanian (Kaunas district) women population with previously diagnosed gestational diabetes mellitus compared to general population

ObjectiveTo determine the association of genetic variants rs7901695, rs7903146, rs7895340, rs11196205, rs12255372 of transcription factor 7 like 2 (TCF7L2) gene and its coherence with metabolic parameters in Lithuanian (Kaunas district) women population with previously diagnosed gestational diabetes mellitus (GDM) and to compare the prevalence of TCF7L2 single nucleotide polymorphism (SNP) results to general population. MethodsWomen with previously diagnosed GDM participated in the study. Anthropometric measurements were taken. Carbohydrate and fat metabolism were evaluated. TCF7L2 SNP common variants (rs7901695, rs7903146, rs7895340, rs11196205, rs12255372) were set.The prevalence of TCF7L2 the same SNP alleles were also evaluated for women of the general population. The results were compared to the main study group (women with previously diagnosed GDM). The results were calculated in a ratio of 1:2. General population group comprised 300 women who were selected from the random sample of the Kaunas city population.Statistical analysis was made with the statistical package IBM SPSS Statistics version 21. Quantitative parametric variables presented as mean and standard deviation, qualitative variables – as absolute numbers and percentage. ANOVA test was used, for the comparison between three or more groups. Quantitative variables were compared using Student’s t-test. Categorical variables were compared using chi-square test. Correlation analysis of parametrical data was performed by Pearson’s correlation. Odds ratios (OR) with 95% CIs were presented. The results were considered statistically significant at p < 0.05. Results158 women with previously (15–47 years ago) diagnosed GDM participated in the study. The mean age of participants was 53.0 ± 8.2 years and 60.2 ± 7.5 years (p < 0.001), BMI – 31.4 ± 7.9 kg/m2 and 29.9 ± 5.8 kg/m2 (p < 0.001) in GDM group and general population respectively. GDM group women had significantly larger waist, hip circumference and waist to hip ratio compared to general population women: 98.9 ± 18.1 cm vs. 89.2 ± 13.3 (p < 0.001), 112.5 ± 14.8 cm vs. 105.6 ± 10.9 cm (p < 0.001), 0.87 ± 0.08 vs. 0.84 ± 0.07 (p < 0.001). There was no significant difference in blood pressure results between groups (p > 0.05).Carbohydrate dysmetabolism was set for 57.6% women with previously diagnosed GDM: 11 (7.0%) were diagnosed with impaired fasting glycemia (IFG), 14 (8.9%) with impaired glucose tolerance (IGT), type 2 Diabetes Mellitus (DM) was diagnosed for 58 (36.7%), DM type 1 for 7 (4.4%), MODY2 (maturity onset diabetes of the young) – 1 (0.6%) patients. TCF7L2 SNPs in women with previously diagnosed GDM and various carbohydrate metabolism groups did not differed (p > 0.05).Body weight, body mass index (BMI), waist and hip circumference in GDM group participants with different TCF7L2 SNP alleles did not differ (p > 0.05). There was no statistically significant difference in fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) results, cholesterol levels and different TCF7L2 SNP alleles in GDM group (p > 0.05).We found higher prevalence of TCF7L2 SNP rs7901695 CC/CT, rs7903146 CT/TT and rs12255372 GT/TT alleles in women previously diagnosed GDM compared to general population women‘s group. The OR of being in GDM group with TCF7L2 SNP: rs7901695 CC/CT alleles, was 1.703 (95% CI 1.153–2.515); rs7903146 CT/TT – 1.708 (95% CI 1.149–2.538); rs12255372 GT/TT – 1.575 (95% CI 1.058–2.343). ConclusionsNo statistically significant difference in glucose, cholesterol levels and different TCF7L2 SNP alleles in GDM group was found. TCF7L2 SNPs did not differed in women with previously diagnosed GDM and various carbohydrate metabolism groups, though a significantly higher incidence of TCF7L2 rs7901695 SNP CC/CT, rs7903146 SNP CT/TT, rs12255372 GT/TT alleles in study subjects compared to the general population women were observed.

Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium

BackgroundAsthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission.MethodsClinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA).ResultsWe identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes.ConclusionWe identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway.

Primer Construction to detect SNP rs11196205 Transcription Factor 7 Like 2 (TCF7L2) Using Amplification Refractory Mutation System (ARMS) PCR to detect Type-2 Diabetes Mellitus

Type-2 Diabetes Mellitus (T2DM) is a metabolic disease characterized by an increase in blood glucose levels. The macrovascular and microvascular complications of T2DM can increase the risk of death in patient. SNP rs11196205 Transcription Factor 7 Like 2 ( TCF7L2 ) gene has been associated with T2DM in several regions like Iceland, Denmark, the United State, and Thailand. SNP rs11196205 is characterized by polymorphism at position 113.047.288 from nucleotide Guanine to Cytosine. Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS PCR) is a method that can be used to detect mutation or polymorphism in a DNA. The aim of this research was to design a specific primer to detect SNP rs11196205 TCF7L2 gene using ARMS PCR. The design of study was a descriptive study to determine the specific primer. The method of the research includes DNA isolation, primer design using Geneious software, amplification of targeted area using ARMS PCR, and DNA sequencing method for bioinformatics study. Based on the research, four primers to detect SNP rs11196205 TCF7L2 gene have been successfully constructed. The primers were rs11196205-F, rs11196205-R, rs11196205-F(C) as a specific primer for C allele, and rs11196205- R(G) to detect G allele, the reaction produced 3 fragments of 856bp, 559bp, and 339bp.

Pivotal Role of Both TNF-α 238G/A and TCF7L2 C/T Gene Polymorphisms in Type 2 Diabetes

Single nucleotide polymorphism (SNP) studies in the promoter region of tumor necrosis factor-alpha (TNF-α (238)) have suggested its role in increased insulin resistance and also in the progression from prediabetes to type 2 diabetes (T2DM). It has been reported that genetic variations in the promoter region regulate TNF-α production and transcription, and they influence susceptibility to inflammatory-related diseases. Impairment of normal functioning of the β-cells of pancreatic islets is one of the main causative factors for the suppression of insulin secretion. TNF-α is among the main stimuli that induce the inflammation in pancreatic islets which lead to the induction of apoptosis in β-cells of pancreatic islets. Transcription factor 7-like 2 (TCF7L2) gene has been found to be one of the most risky genes for prediabetes and progression toT2DM. However, the underlying mechanism of this is still unknown. This is a review article demonstrating the possible mechanisms of both TNF-α G/A 238 and TCF7L2 C/T gene polymorphisms in prediabetes and type 2 diabetes mellitus.

PENGARUH MEDIA TERKONDISI SEL PUNCA MESENSIMAL TERHADAP EKSPRESI GEN TRANSCRIPTION FACTOR 7-LIKE 2 (TCF7L2) TIKUS MODEL DIABETES MELITUS TIPE 2

Diabetes mellitus type 2 is the most common type of diabetes. This study was conducted to determine the effect of Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) in Homeostatic Model Assessment of β-cell function (HOMA-β) value, normal Langerhans cells, and Transcription Factor 7-Like 2 (TCF7L2) gene expression in type 2 diabetic rats model. As many as 27 male Sprague Dawley rats were divided into 3 study research groups: normal control (9 normal rats), diabetic control (9 type 2 diabetic rats, induced by 60 mg/kg BW Streptozotocin and 120 mg/kg BW Nicotinamide i.p.), and treatment (9 type 2 diabetic rats treatment with 0.1 ml/200g BW MSC-CM i.p.). On day 30 after therapy, the expression of TCF7L2 gene was performed with real time-quantitative PCR (RT-qPCR). The HOMA-β value were calculated based on Fasting Insulins (FINs) levels and Fasting Blood Glucose (FBG) levels data from other research team members. Based on results, MSC-CM increases the HOMA-β value and amount of normal Langerhans cells of treatment group that indicates amelioration effect of MSC-CM, but there was no significant difference in TCF7L2 gene expression level between diabetic control and treatment group.

Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes.

PurposePhysical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609.MethodsWe combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness.ResultsHigh PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype.Main ConclusionsOur findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.

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.

Long non-coding RNA CCAT2 promotes prostate cancer cell proliferation and invasion by regulating the Wnt/β-catenin signaling pathway.

Long non-coding RNA colon cancer associated transcript 2 (CCAT2) is dysregulated in a number of different types of human cancer, and affects cancer progression via the Wnt/β-catenin signaling pathway. However, the roles of CCAT2 and the Wnt/β-catenin signaling pathway in prostate cancer (PCa) are not completely understood. The present study aimed to investigate the potential mechanism of CCAT2 in PCa. In the present study, the reverse transcription-quantitative PCR (RT-qPCR) results indicated that CCAT2 expression was significantly upregulated in PCa tissues, and DU145 and PC3 cell lines compared with normal prostate tissues and the epithelial RWPE-1 cell line, respectively. Functional assays indicated that CCAT2 downregulation inhibited DU145 and PC3 cell proliferation, cell cycle, migration and invasion. In addition, the luciferase reporter assay, RT-qPCR and western blotting results indicated that CCAT2 regulated transcription factor 7 like 2 (TCF7L2) expression by binding to microRNA-217. Further western blotting and TOPFlash assays indicated that CCAT2-knockdown inhibited the Wnt/β-catenin signaling pathway in DU145 and PC3 cell lines by inhibiting the expression of TCF7L2. However, CCAT2-knockdown-mediated effects were reversed by the Wnt/β-catenin signaling pathway activator lithium chloride (LiCl). Further cell experiments suggested that LiCl treatment reversed CCAT2-knockdown-mediated inhibition of PCa cell proliferation, cell cycle, epithelial-mesenchymal transition, migration and invasion. Overall, the results indicated that CCAT2 regulated PCa via the Wnt/β-catenin signaling pathway; therefore, CCAT2 may exhibit key role during the progression of PCa and may serve as a therapeutic target for the disease.

Association of TCF7L2 rs7903146 Polymorphism with the Risk of Type 2 Diabetes Mellitus (T2DM) Among Kurdish Population in Erbil Province, Iraq.

The genetic predispositions responsible for developing type 2 diabetes mellitus (T2DM) in the Middle East are poorly understood. The rs7903146 single nucleotide polymorphism (SNP) located in transcription factor 7-like-2 (TCF7L2) gene has been recognized to have a vital role in the development of T2DM disorder. The current study is the first to have researched the possible association between TCF7L2 rs7903146 SNP and T2DM among Kurdish population in Kurdistan region of Iraq. The study included 212 participants, half of them were T2DM patients, and the other half were disease-free and normoglycemic controls. Genotyping was performed by using a high throughput cost and time effective tetra-primer amplification refractory mutation system-polymerase chain reaction (Tetra ARMS-PCR) assay. The rs7903146 genotypic frequencies for CC, CT and TT were 24.5%, 69.8%, and 5.7% in T2DM group respectively, and for the controls were 45.3%, 50.9%, and 3.8% respectively. The frequency of CT genotype was found significantly higher in the cases when compared to the controls (OR = 2.53, 95% CI 1.40-4.57, P value < 0.0019), which indicated that the genotype CT showed risk with diabetes. The T allele showed a high significant frequency in the patients compared to the controls (OR = 1.65, 95% CI 1.10-2.47, P value = 0.014). Our findings demonstrated that the T allele could be a risk factor for increasing the susceptibility of T2DM incidence among the Iraqi Kurdish population.

Embryonic Program Activated during Blast Crisis of Chronic Myelogenous Leukemia (CML) Implicates a TCF7L2 and MYC Cooperative Chromatin Binding.

Chronic myeloid leukemia (CML) is characterized by an inherent genetic instability, which contributes to the progression of the disease towards an accelerated phase (AP) and blast crisis (BC). Several cytogenetic and genomic alterations have been reported in the progression towards BC, but the precise molecular mechanisms of this event are undetermined. Transcription Factor 7 like 2 (TFC7L2) is a member of the TCF family of proteins that are known to activate WNT target genes such as Cyclin D1. TCF7L2 has been shown to be overexpressed in acute myeloid leukemia (AML) and represents a druggable target. We report here that TCF7L2 transcription factor expression was found to be correlated to blast cell numbers during the progression of the disease. In these cells, TCF7L2 CHIP-sequencing highlighted distal cis active enhancer, such as elements in SMAD3, ATF5, and PRMT1 genomic regions and a proximal active transcriptional program of 144 genes. The analysis of CHIP-sequencing of MYC revealed a significant overlapping of TCF7L2 epigenetic program with MYC. The β-catenin activator lithium chloride and the MYC-MAX dimerization inhibitor 10058-F4 significantly modified the expression of three epigenetic targets in the BC cell line K562. These results suggest for the first time the cooperative role of TCF7L2 and MYC during CML-BC and they strengthen previous data showing a possible involvement of embryonic genes in this process.

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.

Acyl-CoA Synthetase Inhibition Protects Clonal Pancreatic Beta-cell from Effects of Chronic Excess Nutrients

Abstract Objectives A single nucleotide polymorphism (SNP) in the transcription factor 7 like 2 (TCF7L2) gene is strongly associated with Type 2 Diabetes (T2D), and deletion of this SNP has been shown to reduce long chain acyl-CoA synthetase 5 (ACSL5) mRNA level. Previous research in our lab has shown chronic exposure to excess nutrients (glucose and fatty acid (FA)) increases lipid droplets in beta-cells and causes basal insulin hypersecretion, left-shifted glucose-stimulated insulin secretion (GSIS), blunted maximal GSIS and reduced insulin content. We tested the efficacy of a known phenylpyrazole-carboxamide compound (herein named ADIPO C) to reduce accumulation of intracellular lipid droplets and reverse the left-shift of GSIS in beta-cells. Methods INS-1832/13 cells were cultured in RPMI media containing 10% FBS (source of FA) and either 4 or 11 mM glucose. Insulin was measured by HTRF assay (CisBio). Intracellular lipid was detected by fluorescence microscopy using Nile red. Fluorescent Bodipy-FA was used as a surrogate FA in both ACS activity assays and lipid incorporation into cells. Oxygen consumption rate was measured using the Seahorse ion flux analyzer and intracellular calcium was measured in fura 2 loaded cells mounted on an Olympus confocal microscope. Results Adipo C (10–25 µM) acutely inhibited acyl-CoA synthetase activity by up to 40% in cell homogenates and similarly reduced FA incorporation into neutral lipids in INS-1 (832/13) cells measured using thin layer chromatography. Longer exposure (72 hrs) to ADIPO C significantly decreased intracellular lipid droplets, right-shifted GSIS and increased insulin content in cells cultured in excess nutrients. Cells cultured in excess nutrients exhibited both increased basal oxygen consumption rate and intracellular calcium oscillations, which were both reduced with 72 hrs ADIPO C incubation. Conclusions Based on these results, we conclude that Adipo C has a protective effect on beta-cells exposed to a glucolipotoxic environment and thus may prove to have therapeutic potential in the prevention/treatment of T2D. Funding Sources No funding sources to report.

TCF7L2 polymorphism a prominent marker among subjects with Type-2-Diabetes with a positive family history of diabetes

The greatest risk of developing type2 diabetes (T2DM) was conferred by rs7903146 SNP of Transcription factor7-like2 (TCF7L2) gene in many ethnic populations. The aim was to investigate the association of TCF7L2 (rs7903146) gene polymorphism among newly diagnosed diabetes subjects with different parental diabetes registry. A total of 171 subjects were categorized into 3 groups based on parental diabetes registry i.e. Conjugal Diabetes Registry (CDR) (n = 50), One Parental Diabetes Registry (OPDR) (n = 56) and Non Parental Diabetes Registry (NPDR) (n = 62) (control group). Kompetitive allele specific PCR (KASP) genotyping assay was used in real time PCR for identifying the genotypes. None of the biochemical parameters showed any significant difference between groups except age at onset of diabetes (p = 0.001). The T allele of TCF7L2 (rs7903146) was associated with significant risk of diabetes. TT genotype which doubles the diabetes risk showed significant association among OPDR whereas in CDR both CT and TT genotypes showed significant association than CC wild type. The ‘T’ allele of TCF7L2 SNP was associated with significant risk when compared between OPDRvsNPDR (OR 2.45, p = 0.003) and CDRvsNPDR (OR 2.82, p = 0.0007). In conclusion, TCF7L2 gene polymorphism and positive family history of diabetes are strongly associated irrespective of the presence of other risk factors among diabetes subjects.

Investigations of Associations between Seven Gene Polymorphisms and Gestational Diabetes Mellitus: Evidence From a Meta-Analysis

Background: Associations of polymorphisms in transcription factor 7 like 2 (TCF7L2), tumor necrosis factor-α (TNF-α), vitamin D receptor (VDR), and interleukin-10 with gestational diabetes mellitus (GDM) were already reported by several publications. Objectives: The aim of this meta-analysis was to better clarify associations between these polymorphisms and GDM by combing the results of all relevant publications. Methods: Eligible publications were searched from Pubmed, Embase, WOS, and CNKI. We used Review Manager to combine the results of individual studies. Results: Thirty-nine studies were included in this study. Combined results revealed that TCF7L2 rs290487, TCF7L2rs7901695, TCF7L2rs7903146, TCF7L2 rs12255372, TNF-α rs1800629, and VDR FokI rs2228570 polymorphisms were all significantly associated with susceptibility to GDM in the total population. In subgroup analyses, we obtained similar positive findings for rs290487, rs7903146, rs1800629, and rs2228570 polymorphisms in Asians, and positive results were also observed for rs7901695, rs7903146, and rs12255372 polymorphisms in Caucasians. Conclusions: Collectively, this meta-analysis proved that TCF7L2 rs290487, TCF7L2rs7901695, TCF7L2rs7903146, TCF7L2 rs12255372, TNF-α rs1800629, and VDR FokI rs2228570 polymorphisms may confer susceptibility to GDM in certain populations.