Integrative Clinical and Functional Characterization of the TCF7L2 rs7903146 Variant Reveals Regulatory Mechanisms Linking Genetic Susceptibility to Oxidative Stress in Type 2 Diabetes

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.