TCF7L2 Polymorphism rs7903146 (C/T) and Gestational Diabetes Influence on Obstetric Outcome: A Romanian Case-Control Study.

Gestational diabetes mellitus (GDM) is one of the most frequent predictors of obstetric outcome among Romanian pregnant women. Thus, we aimed to investigate the role of rs7903146 (C/T) TCF7L2 gene polymorphism in the presence of GDM and to evaluate the influence on maternal-fetal outcomes in a cohort of pregnant women from Northern Transylvania. Our prospective case-control study was performed in a tertiary maternity center on 61 patients diagnosed with GDM and 55 normal pregnant patients. The patients were genotyped for rs7903146 (C/T) polymorphism of the TCF7L2 gene using the PCR-RFLP method between 24 and 28 weeks of gestation. The minor T allele was associated with a high risk of developing GDM (OR 1.71 [95% CI 0.82-3.59]) if both heterozygote and homozygote types were considered. Also, a higher risk of developing GDM was observed in homozygous carriers (OR 3.26 [95% CI 1.10-9.68]). Women with the TT genotype were more likely to require insulin therapy during pregnancy than other genotypes with a 5.67-fold increased risk ([1.61-19.97], p = 0.015). TT homozygote type was significantly associated with fetal macrosomia for birth weights greater than the 95th percentile (p = 0.034). The homozygous TT genotype is associated with an increased risk of developing GDM. Also, rs7903146 (C/T) TCF7L2 variant is accompanied by a high probability of developing insulin-dependent gestational diabetes mellitus (ID-GDM). The presence of at least one minor T allele was associated with a higher risk of fetal macrosomia.

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

BACKGROUND: 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, which may lead to variable complications. It is one of the world's rising health problems. There is emerging evidence that some genetic polymorphisms can impact the risk of evolving T2DM. We try to determine the relationship of (rs7903146) variant of the Transcription factor 7-like 2 (TCF7L2) gene with T2DM and its microvascular complications. METHODS AND RESULTS: 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. CONCLUSION: The T allele of rs7903146 polymorphism of TCF7L2 confers susceptibility to development of T2DM. However, no significant association was found for diabetic complications.

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.

[Association of polymorphisms of genes TCF7L2, FABP2, KCNQ1, ADIPOQ with the prognosis of the development of type 2 diabetes mellitus].

AIM: To study the possibility of using polymorphisms of genesTCF7L2,FABP2,KCNQ1,ADIPOQas markers for predicting the development of type 2 diabetes mellitus (T2D) in the population of Novosibirsk. MATERIALS AND METHODS: On the basis of prospective observation of a representative population sample of residents of Novosibirsk (HAPIEE), 2 groups were formed according to the case-control principle (case people who had diabetes mellitus 2 over 10 years of observation, and control people who did not developed disorders of carbohydrate metabolism). T2D group (n=443, mean age 56.26.7 years, men 29.6%, women 70.4%), control group (n=532, mean age 56.17.1 years, men 32.7%, women 67.3%). DNA was isolated by phenol-chloroform extraction. Genotyping was performed by the method of polymerase chain reaction with subsequent analysis of restriction fragment length polymorphism, polymerase chain reaction in real time. Statistical processing was carried out using the SPSS 16.0 software package. RESULTS AND DISCUSSION: No significant effect of rs1799883 of theFABP2gene, rs2237892 of theKCNQ1gene, and rs6773957 of theADIPOQgene on the risk of developing T2D was found. Genotypes TT and TC rs7903146 of theTCF7L2gene are genotypes for the risk of developing T2D (relative risk RR 3.90, 95% confidence interval CI 2.316.61,p0.001; RR 1.86, 95% CI 1.422.43,p0.001, respectively). The CC genotype rs7903146 of theTCF7L2gene is associated with a protective effect against T2D (RR 0.37, 95% CI 0.290.49,p0.001). When theTCF7L2gene is included in the model for assessing the risk of developing T2D rs7903146, it retains its significance in both men and women. CONCLUSION: The rs7903146 polymorphism of theTCF7L2gene confirmed its association with the prognosis of the development of T2D, which indicates the possibility of considering it as a candidate for inclusion in a diabetes risk meter. Variants of risk meters have been developed to assess the prognosis of the development of diabetes mellitus 2 in men and women aged 4569 years during 10 years of follow-up. The association with the prognosis of the development of T2D polymorphisms rs1799883 of theFABP2gene, rs2237892 of theKCNQ1gene and rs6773957 of theADIPOQgene was not found.

Meta-analysis of association between TCF7L2 polymorphism rs7903146 and type 2 diabetes mellitus.

BACKGROUND: Large scale association studies have found a significant association between type 2 diabetes mellitus (T2DM) and transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146. However, the quality of data varies greatly, as the studies report inconsistent results in different populations. Hence, we perform this meta-analysis to give a more convincing result. METHODS: The articles, published from January 1st, 2000 to April 1st, 2017, were identified by searching in PubMed and Google Scholar. A total of 56628 participants (34232 cases and 22396 controls) were included in the meta-analysis. A total of 28 studies were divided into 4 subgroups: Caucasian (10 studies), East Asian (5 studies), South Asian (5 studies) and Others (8 studies). All the data analyses were analyzed by the R package meta. RESULTS: The significant association was observed by using the dominant model (OR = 1.41, CI = 1.36 - 1.47, p < 0.0001), recessive model (OR = 1.58, CI = 1.48 - 1.69, p < 0.0001), additive model(CT vs CC) (OR = 1.34, CI = 1.28-1.39, p < 0.0001), additive model(TT vs CC) (OR = 1.81, CI = 1.69-1.94, p < 0.0001)and allele model (OR = 1.35, CI = 1.31-1.39, p < 0.0001). CONCLUSION: The meta-analysis suggested that rs7903146 was significantly associated with T2DM in Caucasian, East Asian, South Asian and other ethnicities.

Pilot cohort study on the potential role of TCF7L2 rs7903146 on ischemic heart disease among non-diabetic kidney transplant recipients.

BACKGROUND: TCF7L2 rs7903146 C>T polymorphism is associated with diabetes in the general population but its independent impact on cardiovascular disease is debated. On this basis, we investigated its association with major adverse cardiac events (MACE) in a single-center cohort of non-diabetic kidney transplant recipients (KTRs). METHODS: Patients with pretransplant diabetes were excluded and patients who developed post-transplant diabetes were censored at time of diagnosis. RESULTS: rs7903146 C>T polymorphism appeared to modulate the risk of MACE: 5-year prevalence was 0.8% in CC patients, 7.2% in CT patients and 9.7% in TT patients (P<.001). TCF7L2 rs7903146 was an independent predictor of MACE in a multivariate Cox regression model (for each T allele, HR: 2.99, 95%CI: 1.62-5.52, P<.001), together with history of cardiac ischemic events (HR: 8.69, 95%CI: 3.57-21.16, P<.001), DGF (HR: 2.42, 95%CI: 0.98-5.95, P=.056) and HLA-mismatches (for each mismatch: HR: 1.55, 95%CI: 1.00-2.43, P=.053). Introduction of rs7903146 C>T polymorphism into a model based on these clinical variables significantly increased predictive power for MACE (P=.003). CONCLUSIONS: TCF7L2 rs7903146 T allele may be strongly and independently associated with MACE in non-diabetic KTRs. These findings suggest the possibility of employing this SNP to more accurately stratify cardiological risk in KTRs.

Transcription factor 7-like 2 polymorphism and context-specific risk of metabolic syndrome, type 2 diabetes, and dyslipidemia.

BACKGROUND: The transcription factor 7-like 2 gene (TCF7L2) is an element of the Wnt signaling pathway. There is lack of evidence if TCF7L2 has a functional role in lipid metabolism and regulation of the components constitutes the metabolic syndrome (MetSyn). The aims of this study were to evaluate whether the risk allele of TCF7L2 gene polymorphism is associated with dyslipidemia and MetSyn. MATERIALS AND METHODS: The MetSyn subjects were participated only based on the National Cholesterol Education Program - Third Adult Treatment Panel criteria. In this case-control study, the DNA from MetSyn patients without (n = 90) and with type 2 diabetes (T2D) (n = 94) were genotyped. RESULTS: The results show that the genotype-phenotype for CC, CT/TT of TCF7L2 gene polymorphism correlated with body mass index and waist circumference in MetSyn and MetSyn + T2D subjects (r = -0.949 and r = -0.963, respectively). The subjects that only possess MetSyn but are not diabetics show the 2 h postprandial glucose and fasting blood glucose, glycated hemoglobin significantly lower (P < 0.05) than those subjects have both abnormality. The level of triglyceride in CT/TT carriers in MetSyn was higher than CC carriers (P = 0.025). A comparison with the controls subjects, the frequencies of the T allele in the groups of MetSyn (46.66%) and MetSyn + T2D (47.34%) show significantly different (P < 0.05). The odds ratios for T allele in (MetSyn)/(normal), (MetSyn + T2D)/(normal), and in (MetSyn + T2D)/(MetSyn) were 3.59 (95% confidence interval [CI], 1.33-9.67, P = 0.0093), 3.76 (95% CI, 1.40-10.07, P = 0.0068), and 1.08 (95% CI: 0.55- 2.11, P = 0.834), respectively. CONCLUSION: The results revealed the important insights essential for the role of TCF7L2 that the T allele of TCF7L2 plays a significant role in the susceptibility to dyslipidemia, MetSyn, and T2D.

Genetic Association of Transcription Factor 7-Like-2 rs7903146 Polymorphism With Type 2 Diabetes Mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) mainly results from the inability of muscle, fat, and liver cells to uptake glucose due to insulin resistance or deficiency of insulin production by the pancreas. Predisposition to T2DM may be due to environmental, hereditary, or both factors. Although there are many genes involved in causing T2DM, transcription factor 7-like-2 gene (TCF7L2) rs7903146 (C/T) single nucleotide polymorphism (SNP) found in genome-wide association studies (GWAS) is susceptible to T2DM. TCF7L2 is involved in pancreatic beta cell proliferation and differentiation via the Wnt signaling mechanism. OBJECTIVES: To find the genetic association of TCF7L2 rs7903146 (C/T) gene polymorphism in patients with T2DM. METHODS: A case-control study was conducted on 194 T2DM patients recruited from the endocrinology department at Indira Gandhi Institute of Medical Sciences, Patna, and 180 non-diabetic healthy controls that were age and sex-matched with the patients. All clinical examination and biochemical investigations like glycosylated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol; and determination of TCF7L2 gene polymorphism by allele-specific polymerase chain reaction (AS-PCR) were carried out for each subject. RESULTS:  The T allele of the rs7903146 (C/T) SNP was associated with a two-fold higher risk of T2DM and the heterozygous genotype (CT) with a 1.96 times higher risk. CONCLUSION: There is a high association of this SNP with the development of T2DM in the eastern Indian population. Serial monitoring of HbA1c should be done in an individual having this type of polymorphism for early detection of T2DM to prevent future complications.

Association of TCF7L2 Variants in Type 2 Diabetes Mellitus with Hypertriglyceridemia - A Case-Control Study.

Background: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition involving various genetic and environmental factors leading to impaired insulin secretion, resulting in hyperglycemia. The transcription factor 7-like 2 (TCF7L2) gene is an element of the Wnt signaling pathway that plays an important role in glucose and lipid metabolism. The aim of this study is to evaluate the association of TCF7L2 rs7903146 and rs12255372 polymorphisms in T2DM with hypertriglyceridemia. Methods: We investigated the effect of rs7903146 and rs12255372 on T2DM with high triglyceride (TG) levels in 60 patients and 20 controls. The anthropometric measurements and biochemical tests were assessed. Peripheral blood samples were collected, and genomic DNA was extracted. The genotyping of TCF7L2 polymorphisms was carried out using polymerase chain reaction (PCR)-based direct sequencing and allele-specific PCR methods. The T2DM patients and controls were compared by means of the t-test, Chi-square test, odds ratio (OR), and 95% confidence interval (CI) using Epi Info v7. Results: The HbA1c was found to be 9.7 ± 2.1 and 5.4 ± 0.5% in patients and controls, respectively. The average TG levels (P < 0.005) in patients were 205.2 ± 145.7 and 106.4 ± 27.4mg/dl in controls. Significant evidence of association was found in T2DM patients having high TG levels with rs7903146 CT/TT (OR: 4.89; P = 0.0105) and rs12255372 GT/TT (OR: 5.23; P = 0.0101) genotypes when compared to controls. Conclusion: The results of this study show that TCF7L2 rs7903146 CT/TT and rs12255372 GT/TT genotypes are significantly associated with the risk of hypertriglyceridemia in individuals with T2DM among the studied population.

Saudi Community-Based Screening Study on Genetic Variants in ß-Cell Dysfunction and Its Role in Women with Gestational Diabetes Mellitus.

BACKGROUND: Diabetes (hyperglycemia) is defined as a multifactorial metabolic disorder in which insulin resistance and defects in pancreatic ß-cell dysfunction are two major pathophysiologic abnormalities that underpin towards gestational diabetes mellitus (GDM). TCF7L2, KCNQ1, and KCNJ11 genes are connected to the mechanism of ß-cell dysfunction. The purpose of this study was to investigate the genes associated with ß-cell dysfunction and their genetic roles in the rs7903146, rs2237892, and rs5219 variants in Saudi women diagnosed with type 2 diabetes mellitus and GDM. MATERIALS AND METHODS: In this case-control study, 100 women with GDM and 100 healthy volunteers (non-GDM) were recruited. Genotyping was performed using polymerase chain reaction (PCR), followed by restriction fragment length analysis. Validation was performed using Sanger sequencing. Statistical analyses were performed using multiple software packages. RESULTS: Clinical studies showed a ß-cell dysfunction positive association in women with GDM when compared to non-GDM women (p < 0.05). Both rs7903146 (CT vs. CC: OR-2.12 [95%CI: 1.13-3.96]; p = 0.01 & T vs. C: (OR-2.03 [95%CI: 1.32-3.11]; p = 0.001) and rs5219 SNPs (AG vs. AA: OR-3.37 [95%CI: 1.63-6.95]; p = 0.0006 & G vs. A: OR-3.03 [95%CI: 1.66-5.52]; p = 0.0001) showed a positive association with genotype and allele frequencies in women with GDM. ANOVA analysis confirmed that weight (p = 0.02), BMI (p = 0.01), and PPBG (p = 0.003) were associated with rs7903146 and BMI (p = 0.03) was associated with rs2237892 SNPs. CONCLUSIONS: This study confirms that the SNPs rs7903146 (TCF7L2) and rs5219 (KCNJ11) are strongly associated with GDM in the Saudi population. Future studies should address the limitations of this study.

Possible Role of rs7903146 Polymorphism of the Transcription Factor 7-Like 2 Gene in Genetic Predisposition to Type 2 Diabetes.

<b>Background and Objective:</b> The association of rs7903146 polymorphism of TCF7L2 gene with Type 2 diabetes mellitus found almost in all ethnic groups. Therefore, the current study focused on estimating this association in the Azerbaijan population for the 1st time. <b>Materials and Methods:</b> A study was conducted on 110 patients with Type 2 diabetes mellitus and 115 healthy controls. The biochemical parameters were analyzed and calculated with an independent t-test and Fisher exact test. DNA extracted from the blood samples run in PCR. PCR was used to detect the presence of TCF7L2 rs7903146 C/T polymorphism and the products of the PCR were visualized in a 1.5% gel electrophoresis. <b>Results:</b> According to the obtained data, T allele and TT genotype of rs7903146 polymorphism strongly correlated with the risk for Type 2 diabetes (odds ratio of 1.68 for T allele and p = 0.007, odds ratio of 3.9 for TT genotype, p = 0.0028). These results were adjusted by applying the recessive model (p = 0.003). Moreover, the biochemical parameters also show a significant difference in the fasting glucose level (p = 0.0001), fasting insulin (p = 0.0001), BMI (p = 0.0002) and age (p = 0.015) inpatient and control groups. <b>Conclusion:</b> Based on the results, the TCF7L2 rs7903146 (C>T) polymorphism is the genetic risk factor related to Type 2 diabetes in the Azerbaijan population.

Role of rs7903146 polymorphism and adropin serum level in patients with diabetes mellitus; a case-control study from Isfahan, Iran.

BACKGROUND: Type-2 diabetes mellitus (T2DM) is the common endocrinopathy which characterised by insulin resistance, insufficient expression or secretion of insulin and decrement of insulin effectiveness. Although T2DM has unknown aetiology, the strongest susceptible gene in this disease is TCF7L2. Adropin peptide may have roles in T2DM pathogenesis due to several roles in glucose tolerance, decrement of insulin resistance, lipid metabolism and energy homoeostasis. AIM: To evaluate the serum level of adropin in T2DM patients and comparing with healthy individuals as well as assessing frequency of rs7903146 genotypes/alleles in patients and control groups. METHODS: We analysed the frequency of rs7903146 genotypes/alleles in 93 patients with T2DM disease and 53 healthy individuals by the method of polymerase chain reaction-restriction fragment length polymorphism analysis. The serum level of adropin was measured by using enzyme-linked immunosorbent assay technique. RESULTS: The mean serum level of adropin was 12.32 ± 2.98 and 9.51 ± 2.73 in patients and control groups, respectively (p value < .001). Also, there were significant difference in frequency of genotypes and alleles of rs7903146 in patients and controls groups (p < .001). The rs7903146T/T and rs7903146C/T genotypes increased risk of T2DM disease (OR: 6.035 and OR: 3.082, respectively). Interestingly, the highest level of adropin was detected in T2DMpatients with rs7903146T/T genotype. CONCLUSION: Our analysis showed higher level of adropin in T2DM patients and increased risk of T2DM with rs7903146T/T and rs7903146C/T genotypes.

Association of TCF7L2, CASC8 and GREM1 Polymorphisms in Patients with Colorectal Cancer and Type II Diabetes Mellitus.

BACKGROUND: The aim of the study is to explore the association between the TCF7L2 rs7903146, CASC8 rs6983267 and GREM1 rs16969681 polymorphisms in patients diagnosed with type 2 diabetes mellitus (T2DM) and colorectal cancer. METHODS: Sixty individuals were enrolled in this case-control study: thirty with colorectal cancer and type II diabetes mellitus (T2DM) and thirty healthy control individuals. Real-time PCR was used to determine the genotypes of TCF7L2 rs7903146, CASC8 rs 6983267 and GREM1 rs16969681 in patients with CRC and T2DM and in patients without T2DM and CRC. The Hardy-Weinberg equilibrium was determined in the control group for the genotype distribution of every polymorphism. RESULTS: People carrying the TT genotype of rs7903146, rs6983267 and rs1696981 had a significant association with T2DM and CRC. Moreover, the people with the TT genotype of rs1696981 had a greater risk for T2DM and CRC (OR = 7, CI 0.397-23.347). CONCLUSIONS: TCF7L2 rs7903146, CASC8 rs6983267 and GREM1 rs16969681 could be risk factors for the association of T2DM with CRC.

TCF7L2 gene polymorphism in populations of f ive Siberian ethnic groups.

Investigation of the frequencies of functionally signif icant gene variants in the context of medical biology and gene geography is a relevant issue for studying the genetic structure of human populations. The transition from a traditional to an urbanized lifestyle leads to a higher incidence of civilizational diseases associated with metabolic disorders, including type 2 diabetes mellitus. The goal of the present paper is to analyze the frequencies of functionally signif icant gene alleles in the metabolic prof iles of indigenous Siberian peoples to identify the gene pool resilience, evaluate the susceptibility of various ethnic groups to metabolic disorders under changing environmental conditions, and predict the epidemiological situation that may occur in the near future. The study was performed in the monoethnic samples of eastern and western Buryats, Teleuts, Dolgans, and two territorial groups of Yakuts. A real-time PCR was used to determine the frequencies of single nucleotide polymorphisms (SNPs) G103894T, rs12255372, and C53341T, rs7903146 in the TCF7L2 gene. The results obtained were compared to the frequencies identif ied for Russians from Eastern Siberia and the values available in the literature. The frequencies of the polymorphic variants studied in the samples from the indigenous Siberian peoples place them in between Caucasian and East Asian populations, following the geographic gradient of polymorphism distribution. A signif icantly lower occurrence of type 2 diabetes risk alleles TCF7L2 (103894T) and TCF7L2 (53341T) in the samples of indigenous Siberian peoples compared to Russians was observed, which agrees with their lower susceptibility to metabolic disorders compared to the newcomer Caucasian population. Taking into account urbanization, a reduced growth in type 2 diabetes incidence may be predicted in indigenous Siberian peoples, i. e. Buryats, Yakuts, Dolgans, and Teleuts, compared to the newcomer Caucasian population. A further study of population structure with respect to different metabolic prof ile genes is required to better understand the molecular genetic foundations of the adaptive potential of indigenous Siberian peoples.

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.

TCF7L2 rs7903146 polymorphism association with diabetes and obesity in an elderly cohort from Brazil.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and obesity are complex pandemic diseases in the 21st century. Worldwide, the T allele rs7903146 in the TCF7L2 gene is recognized as a strong GWAS signal associated with T2DM. However, the association between the C allele and obesity is still poorly explored and needs to be replicated in other populations. Thus, the primary objectives of this study were to evaluate the TCF7L2 rs7903146 association with T2DM according to BMI status and to determine if this variant is related to obesity and BMI variation in a cohort of elderly Brazilians. METHODS: A total of 1,023 participants from an elderly census-based cohort called SABE (Saúde, Bem Estar e Envelhecimento-Health, Well-Being and Aging) were stratified by BMI status and type 2 diabetes presence. The TCF7L2 genotypes were filtered from the Online Archive of Brazilian Mutations (ABraOM-Online Archive of Brazilian Mutations) database, a web-based public database with sequencing data of samples of the SABE's participants. Logistic regression models and interaction analyses were performed. The BMI variation (∆BMI) was calculated from anthropometric data collected in up to two time-points with a ten-year-assessment interval. RESULTS: The association between the rs7903146 T allele and T2DM was inversely proportional to the BMI status, with an increased risk in the normal weight group (OR 3.36; 95% CI [1.46-7.74]; P = 0.004). We confirmed the T allele association with risk for T2DM after adjusting for possible confound ing variables (OR 2.35; 95% CI [1.28-4.32]; P = 0.006). Interaction analysis showed that the increased risk for T2DM conferred by the T allele is modified by BMI (P interaction = 0.008), age (P interaction = 0.005) and gender (P interaction = 0.026). A T allele protective effect against obesity was observed (OR 0.71; 95% CI [0.54-0.94]; P = 0.016). The C allele increased obesity risk (OR 1.40; 95% CI [1.06-1.84]; P = 0.017) and the CC genotype showed a borderline association with abdominal obesity risk (OR 1.28; 95% CI [1.06-1.67]; P = 0.045). The CC genotype increased the obesity risk factor after adjusting for possible confounding variables (OR 1.41; 95% CI [1.06-1.86]; P = 0.017). An increase of the TT genotype in the second tertile of ∆BMI values was observed in participants without type 2 diabetes (OR 5.13; 95% CI [1.40-18.93]; P = 0.009) in the recessive genetic model. CONCLUSION: We confirmed that the rs7903146 is both associated with T2DM and obesity. The TCF7L2 rs7903146 T allele increased T2DM risk in the normal weight group and interacted with sex, age and BMI, while the C allele increased obesity risk. The TT genotype was associated with a lesser extent of BMI variation over the SABE study's 10-year period.

Dietary Intake and TCF7L2 rs7903146 T Allele Are Associated with Elevated Blood Glucose Levels in Healthy Individuals.

INTRODUCTION: Type 2 diabetes (T2D) is a leading cause of global mortality with diet and genetics being considered amongst the most significant risk factors. Recently, studies have identified a single polymorphism of the TCF7L2 gene (rs7903146) as the most important genetic contributor. However, no studies have explored this factor in a healthy population and using glycated haemoglobin (HbA1c), which is a reliable long-term indicator of glucose management. This study investigates the association of the genetic polymorphism rs7903146 and dietary intake with T2D risk in a population free of metabolic disease. METHODS: T2D risk was assessed using HbA1c plasma concentrations and dietary intake via a validated Food Frequency Questionnaire in 70 healthy participants. RESULTS: T allele carriers had higher HbA1c levels than the CC group (32.4 ± 7.2 mmol/mol vs. 30.3 ± 7.6 mmol/mol, p = 0.005). Multiple regression reported associations between diet, genotype and HbA1c levels accounting for 37.1% of the variance in HbA1c (adj. R2 = 0.371, p < 0.001). The following macronutrients, expressed as a median percentage of total energy intake (TEI) in the risk group, were positively associated with HbA1c concentration: carbohydrate (≥39% TEI, p < 0.005; 95% CI 0.030/0.130) protein (≥21% TEI, p < 0.005, 95% CI 0.034/0.141), monounsaturated (≥15% TEI p < 0.05, 95% CI 0.006/0.163) and saturated fatty acids (≥13% TEI; p < 0.05, 95% CI 0.036/0.188). CONCLUSION: Carriers of the T allele showed significantly higher levels of HbA1c compared to non-carriers. Dietary intake affected T2D risk to a greater extent than genetic effects of TCF7L2rs7903146 genotype in a healthy population. The study focus on healthy individuals is beneficial due to the applicability of findings for T2D screening.

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?

BACKGROUND: Genetic 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. RESULTS: We 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). CONCLUSION: The 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).

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.

Genetic associations between Transcription Factor 7 Like 2 rs7903146 polymorphism and type 2 diabetes mellitus: a meta-analysis of 115,809 subjects.

BACKGROUND: Some genetic association studies tried to investigate potential associations of Transcription Factor 7 Like 2 (TCF7L2) rs7903146 polymorphism with type 2 diabetes mellitus (T2DM). However, the results of these studies were not consistent. Thus, we performed the present meta-analysis to explore associations between TCF7L2 rs7903146 polymorphism and T2DM in a larger pooled population. METHODS: Systematic literature research of PubMed, Web of Science and Embase was performed to identify eligible studies for pooled analyses. I2 statistics were employed to assess between-study heterogeneities. If I2 was greater than 50%, random-effect models (REMs) would be used to pool the data. Otherwise, fixed-effect models (FEMs) would be applied for synthetic analyses. RESULTS: Totally 68 studies with 115,809 subjects were included for analyses. The pooled analyses showed that TCF7L2 rs7903146 (dominant model: p < 0.0001; recessive model: p < 0.0001; over-dominant model: p < 0.0001; allele model: p < 0.0001) polymorphism was significantly associated with susceptibility to T2DM in overall population. Further subgroup analyses revealed similar significant findings in both Asians and Caucasians. CONCLUSIONS: In conclusion, our findings supported that TCF7L2 rs7903146 polymorphism could be used to identify individuals at high risk of developing T2DM in Asians and Caucasians.