The Role of VEGFA in T2DM-Nephropathy: A Genetic Association Study and Meta-Analysis

Background: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, arising from complex interactions between metabolic, hemodynamic, and genetic factors. Among candidate genes, vascular endothelial growth factor A (VEGFA) has been extensively investigated due to its role in endothelial homeostasis and microvascular complications of diabetes. The present study aimed to examine the association of VEGFA polymorphisms with DN in a Greek population and to perform a comprehensive meta-analysis of available evidence. Methods: A case-control study was conducted, including 197 patients with type 2 diabetes mellitus (T2DM) and DN, 155 diabetic patients without nephropathy, and 246 healthy controls. Ten tagging single-nucleotide polymorphisms (SNPs) across VEGFA were genotyped. Statistical analyses employed the generalized odds ratio (OR_G). To contextualize these findings, a meta-analysis of 13 eligible studies was performed, encompassing 7520 cases, 6951 diabetic controls, and 1718 healthy controls. Results: Of the tested variants in the present case-control study, only rs833070 was significantly associated with DN across all comparisons. Nine VEGFA variants were evaluated in meta-analysis, with rs2146323 showing a protective effect (allelic OR = 0.85; 95% CI: 0.76-0.95), while other variants yielded non-significant associations. Conclusions: Overall, the data suggest that VEGFA polymorphisms, particularly rs833070 and rs2146323, contribute to genetic susceptibility to DN, although population-specific differences and heterogeneity across studies remain substantial. Future research in large, ethnically diverse cohorts with functional analyses is warranted to clarify causal mechanisms and enable the integration of VEGFA genetic variation into risk stratification and personalized therapeutic strategies.