VEGFA ‐centric angiogenic genetic variants drive hypertension and dyslipidaemia susceptibility in type 2 diabetes mellitus: A multilocus synergistic cohort study

Background The interplay between angiogenic genetic variants and metabolic‐vascular comorbidities in type 2 diabetes mellitus (T2DM) remains poorly elucidated. This cohort study investigated the synergistic effects of VEGFA‐centric polymorphisms on hypertension (HTN) and dyslipidaemia (DYS) susceptibility in T2DM. Methods We enrolled 440 individuals stratified into three groups: T2DM‐only ( n = 258), T2DM+HTN (T2MH, n = 130) and T2DM+HTN+DYS (T2MH‐DYS, n = 52). Genotyping of VEGFA rs3025020, ANGPT2 rs11137037/rs2442598, TGFB1 rs1800469 and AGTR1 rs5182 was performed using ligase‐mediated hybridization and multiplex PCR. Phenotypic profiling included metabolic, haemodynamic and inflammatory biomarkers. Results The T2MH‐DYS group exhibited severe metabolic dysregulation, with elevated fasting glucose (12.60 ± 7.62 vs. 7.93 mmol/L, p = 0.017), triglycerides (median 2.48 vs. 1.68 mmol/L, p < 0.001) and systemic inflammation (CRP: 2.65 vs. 1.79 mg/L, p = 0.016). VEGFA rs3025020‐TT genotype frequency was significantly enriched in T2MH‐DYS (17.3% vs. 3.9% in T2DM, recessive model p < 0.001), conferring a 3.49‐fold comorbidity risk (95% CI: 1.10–11.14, p = 0.034). ANGPT2 rs2442598‐CC genotype demonstrated borderline protective effects (OR = 0.46, p = 0.057), while AGTR1 rs5182‐TT correlated with milder HTN (Grade I: 72.2% vs. Grade III: 46.6%, p = 0.008). Haplotype analysis revealed synergistic risks: C‐C‐T (AGTR1‐ANGPT2‐VEGFA) increased T2MH‐DYS susceptibility 3.58‐fold ( p = 0.0019), whereas C‐T‐C exhibited protection (OR = 0.333, p = 0.013). Conclusion These findings underscored VEGFA rs3025020 as a genetic hub coordinating multilocus angiogenic dysregulation, driving HTN and DYS pathogenesis in T2DM. Our results highlight the potential for genotype‐guided anti‐angiogenic therapies to mitigate metabolic–vascular deterioration in high‐risk diabetic populations.