Integrative Clinical and Functional Characterization of the TCF7L2 rs7903146 Variant Reveals Regulatory Mechanisms Linking Genetic Susceptibility to Oxidative Stress in Type 2 Diabetes
Predictive evidence was provided suggesting that rs7903146 may have tissue-specific regulatory relevance and may be indirectly linked to metabolic and WNT/β-catenin signaling pathways, and the proposed regulatory mechanisms require experimental validation.
Abstract
Background: The transcription factor 7-like 2 (TCF7L2) gene is one of the strongest genetic determinants of type 2 diabetes mellitus (T2DM), with the rs7903146 (C > T) polymorphism consistently associated with impaired insulin secretion and glucose dysregulation. This study investigated the associations between the TCF7L2 rs7903146 polymorphism, glycemic control, oxidative stress biomarkers, and T2DM susceptibility, integrating bioinformatic analyses to explore the functional significance of this variant. Methods: This case–control study included 200 patients with T2DM, 100 prediabetic individuals, and 120 healthy controls. Genotyping of rs7903146 was performed using TaqMan SNP assays. Biochemical analyses included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid profile, and oxidative stress biomarkers, including superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA). Bioinformatic analyses included population frequency analysis, regulatory annotation, chromatin accessibility assessment, expression quantitative trait locus (eQTL) analysis, protein interaction network construction, and pathway enrichment analyses to investigate the functional consequences of rs7903146. Results: The T allele frequency was markedly higher in T2DM patients (33.5%) and prediabetic individuals (30%) than in controls (13.3%) (p < 0.001). T2DM susceptibility increased under allelic (OR = 3.27, 95% CI: 2.14–5.01), dominant (OR = 3.9, 95% CI: 2.37–6.42), and recessive (OR = 6.92, 95% CI: 1.59–30.07) models (p < 0.01). T2DM patients also showed significantly lower superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, lower total antioxidant capacity (TAC), and higher MDA levels (p < 0.001). T allele carriers had poorer glycemic control and greater oxidative stress. Bioinformatic analyses showed that rs7903146 resides within an active intronic regulatory region with chromatin accessibility, enhancer-associated histone marks, transcription factor occupancy, and candidate cis-regulatory elements. eQTL analyses showed tissue-specific effects on TCF7L2 expression, while network and pathway analyses highlighted WNT signaling, β-catenin transcriptional complexes, and metabolic regulation and oxidative stress pathways. Conclusions: The TCF7L2 rs7903146 polymorphism was significantly associated with T2DM susceptibility, impaired glycemic regulation, and altered oxidative stress biomarkers. Bioinformatic analyses provided predictive evidence suggesting that rs7903146 may have tissue-specific regulatory relevance and may be indirectly linked to metabolic and WNT/β-catenin signaling pathways. However, because of the observational case–control design, these findings do not establish causality, and the proposed regulatory mechanisms require experimental validation.
Background: Type 2 diabetes mellitus (T2DM) is a persistent metabolic disorder characterised by elevated blood glucose levels and influenced by both genetic and environmental factors.
Aim: This study investigated the association of TCF7L2 SNPs rs1790314 and rs12255372 with renal and inflammatory markers in type 2 diabetes mellitus.
Methods: This cross-sectional study examined biochemical markers and the TCF7L2 SNPs rs12255372 and rs1790314 in 140 patients with T2DM attending the diabetic clinics of Rivers State University Teaching Hospital (RSUTH) and the University of Port Harcourt Teaching Hospital (UPTH), together with 40 non-diabetic controls. Biochemical parameters, including fasting blood glucose (FBG), HbA1c, C-peptide, insulin, HOMA-IR, cystatin C, estimated glomerular filtration rate (eGFR), creatinine, urea, and electrolytes, were measured using colourimetric and ELISA methods. The TCF7L2 variants were genotyped using BigDye Terminator sequencing. Data on these parameters and the TCF7L2 genotypes were analysed using GraphPad Prism, SPSS, and Excel. Descriptive statistics were presented as means ± SD, while inferential analyses included Student's t-test, Pearson's correlation, linear regression, and one-way ANOVA. Statistical significance was set at p < 0.05.
Results: The study found an increasing prevalence of T2DM in Port Harcourt in recent years, with rates of 23% in males and 21% in females, and a glycaemic control rate of 38.75%. The TCF7L2 genotype distribution showed that 32.5% had the CC genotype and 11.25% had the CT/TT genotypes at rs1790314, whereas 41.25% had the GG genotype and 3.75% had the GT/TT genotypes at rs12255372. Abnormalities such as hyponatraemia, low chloride levels, and hyperkalaemia were observed in patients with poorly controlled T2DM. Physical activity was associated with better cardiovascular health, as indicated by lower cardiac troponin I (cTnI) levels. Standard antidiabetic drugs, including metformin (Glucophage) and sulfonylureas (Amaryl), were associated with dyslipidaemia, particularly in males, characterised by reduced HDL-C and triglyceride levels and increased atherogenic ratios such as TC/TG. An association was also found between chloride levels and the T allele at rs1790314. BMI and WHR did not correlate with the CT/TT polymorphisms at rs1790314 or the GT/TT polymorphisms at rs12255372, although both were higher in individuals with T2DM carrying the TCF7L2 variants. The rs1790314 CT/TT mutation was associated with higher triglyceride, TC/TG, and TC/HDL ratios and lower HDL-C levels. Insulin resistance, indicated by increased C-peptide levels, was observed in rs1790314 CT/TT carriers, while renal abnormalities associated with rs12255372 GT/TT correlated with cystatin C. Overall, TCF7L2 variants were associated with dyslipidaemia, elevated cystatin C, and increased C-peptide levels. Patients with mutant T alleles in both variants had significantly higher HbA1c, WHR, BMI, lipid, atherogenic marker, and troponin I levels.
Conclusion: The findings suggest that increased insulin resistance and impaired cellular uptake occurred alongside significantly higher C-peptide levels in individuals with the CT/TT polymorphic variants of transcription factor 7-like 2 (TCF7L2) rs1790314. Furthermore, renal abnormalities were associated with the TCF7L2 rs12255372 GT/TT polymorphic variant, which was positively associated with cystatin C in participants with type 2 diabetes mellitus (T2DM) who expressed TCF7L2.
Idoko Roseline, B. Holy, Onwuli Donatus et al.· Asian Journal of Medicine an...· 0 citations
BACKGROUND/AIMS
DNA methylation is a critical epigenetic mechanism involved in the regulation of gene expression, including genes implicated in glucose metabolism. Despite growing evidence indicating that epigenetic mechanisms are involved in the pathogenesis and progression of type 2 diabetes mellitus (T2DM), available data remain limited. This study analyzed the genetic association of two single-nucleotide polymorphisms (SNPs) in the DNA methyltransferase 3A (DNMT3A) gene, rs11683424 and rs1550117, with T2DM susceptibility and investigated their potential associations with global DNA methylation.
METHODS
Total antioxidant status (TAS) and total oxidant status (TOS) were evaluated, the oxidative stress index (OSI) was calculated, and diabetes-related parameters were assessed in T2DM patients and healthy controls, including HbA1c, fasting blood glucose (FBG), insulin, insulin sensitivity (IS), and insulin resistance (IR). Global DNA methylation was determined, and rs11683424 and rs1550117 were genotyped. Associations between metabolic and oxidative stress parameters, global DNA methylation, DNMT3A genotypes, and T2DM status were statistically analyzed.
RESULTS
T2DM patients exhibited significantly higher HbA1c, FBG, insulin, and IR levels than healthy controls (p=0.001), whereas IS was significantly lower (p=0.001). TAS, TOS, and OSI were significantly increased in T2DM patients compared with controls (p=0.001), as was global DNA methylation (p=0.001). In patients, a weak but statistically significant inverse correlation was observed between 5mC levels and BMI. Global methylation showed weak inverse associations with TAS and TOS; however, these associations did not reach statistical significance. No significant associations (p>0.05) were observed between 5mC levels and the other studied biomarkers. Neither regression model for predictors of global DNA methylation was statistically significant in T2DM patients (F(5,94)=0.852, p=0.516) or healthy controls (F(4,95)=0.592, p=0.669), and all variance inflation factor (VIF) values were <2.0. For rs11683424, the CT genotype was detected in 15.6% of T2DM patients compared with 2.6% of controls (OR=6.81, 95% CI=1.50-31.25, χ²=7.902, p=0.005). The T allele was present at frequencies of 7.8% and 1.3%, respectively (χ²=7.502, p=0.006). In contrast, rs1550117 was not significantly associated with T2DM. Linkage disequilibrium analysis indicated incomplete or moderate linkage disequilibrium between the two SNPs. The CG haplotype was the most common in both groups, whereas the TG and TA haplotypes were enriched among patients and showed increased disease odds, particularly TG (OR=7.89); however, neither association reached statistical significance. Genotype-phenotype analyses revealed only limited differences in global DNA methylation among the investigated genotypes.
CONCLUSION
T2DM was associated with altered oxidative stress parameters and increased global DNA methylation. The findings further indicate a potential association between DNMT3A rs11683424 and T2DM susceptibility, whereas rs1550117 was not significantly associated with disease status. However, the data do not establish a direct relationship between the investigated DNMT3A variants, oxidative stress, and global DNA methylation. These findings warrant validation in larger, multi-ethnic cohorts.
Ali Al-lami, H. Al-Musawi, Hiba Abdulameer Mohammed et al.· Cellular Physiology and Bioc...· 0 citations
OLR1 rs11053646 SNP does not appear to be associated with T2D risk in Saudi adults, and small sample size may have limited statistical power to detect potential associations.
V. Vennu· Endocrine, Metabolic & Immun...· 0 citations
Background: Phospholipid transfer protein (PLTP) facilitates lipid transfer among plasma lipoproteins, but the contribution of this protein to coronary heart disease (CHD) remains controversial. In this context, evaluating single nucleotide polymorphisms (SNPs) in the PLTP gene, specifically rs6065904 A/G and rs378114 T/C, may hold clinical utility for predicting CHD risk. Nevertheless, currently evidence on the association between these variants and cardiovascular outcomes remains scarce. To address this gap, we investigated whether the rs6065904 A/G and rs378114 T/C SNPs of the PLTP gene are associated with the incidence of acute coronary syndrome (ACS) and explored whether this potential relationship is mediated by plasma lipid levels. Methods: This study included 2377 Mexican Mestizos (1378 ACS patients and 999 control individuals). The PLTP SNPs (rs6065904 A/G, and rs378114 T/C) were genotyped using TaqMan assays on Real-Time PCR equipment, following the manufacturer’s cycling protocol. Results: Logistic regression analysis under different inheritance models revealed that homozygosity for the rs6065904 AA and rs378114 TT genotypes was associated with a significant increased risk of ACS. In subgroup analysis restricted to ACS patients, both genotypes were also significantly associated with altered triglyceride and glucose levels. Complementary bioinformatic analysis using the Genotype-Tissue Expression (GTEx) Project suggested that these genotype–phenotype associations might be mechanistically linked to reduced PLTP mRNA expression. Conclusions: In summary, the rs6065904 A/G and rs378114 T/C SNPs in the PLTP gene are associated with ACS risk, and with circulating triglyceride and glucose levels.
Gilberto Vargas-Alarcón, Ó. Pérez-Méndez, R. Posadas-Sánchez et al.· Biomedicines· 0 citations
Objective: This study aims to evaluate the association of the insulin receptor substrate 1 (IRS1) rs2943640 single nucleotide polymorphism (SNP) with the effectiveness of glibenclamide therapy in Iraqi diabetic patients treated with glibenclamide.
Methods: This cross-sectional study was conducted in Karbala City, located in central Iraq, from September 2024 to December 2025, and enrolled a total of 160 individuals with a confirmed diagnosis of type 2 diabetes mellitus (T2DM). Venous blood samples were obtained from all participants for the genotyping of the rs2943640 (A/C) SNP and assessment of biochemical parameters, including glycemic indices, lipid profiles, and liver and kidney functions.
Results: The genotype frequencies of rs2943640 A/C are 30 % for AA, 61.9 % for AC, and 8.1 % for CC. No statistically significant differences between the three patient groups in biochemical parameters, including glycemic indices, lipid profiles, kidney functions, and aspartate aminotransferase (AST), while alanine aminotransferase (ALT) showed a significant difference among the patient groups.
Conclusion: Our results show no statistically significant association between IRS1 rs2943640 (A/C) SNP and therapeutic response to glibenclamide in Iraqi T2DM patients.
Mohammed Mahmood Abedalhussein, Mohammed Ibrahim Rasool, Suzanne Jubair Abbas· International Journal of App...· 0 citations
APOC1 rs4420638 and CXCL8 rs4073 seem to be associated with DN risk in Tunisian T2DM patients both individually and within multilocus genetic profiles.
Amira Moussa, J. Methnani, Refka Hassine et al.· Endocrine· 0 citations
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