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.