ENHO and EDN1 variants link adropin–endothelin-1 imbalance with early vascular aging in adults with and without type 2 diabetes

Background Early vascular aging (EVA) is common in type 2 diabetes, yet its inherited determinants remain undefined. This study examined the associations of ENHO and EDN1 genetic variation with circulating adropin, endothelin-1, their relative imbalance, and early vascular aging in adults with and without T2DM. Methods This study included 300 adults aged 25–55 years, comprising 150 participants with T2DM and 150 age- and sex-matched controls. Participants were further classified as having Early vascular aging (EVA) (n=116) or Normal vascular aging (NVA) (n=184) using age-referenced estimated pulse wave velocity. ENHO rs2281997 and rs72735260, and EDN1 rs5370 and rs2070699 were genotyped by HRM analysis with Sanger confirmation. Gene-specific and total genetic risk scores (GRS) were tested against adropin, endothelin-1, the adropin–endothelin-1 imbalance index (AEI), EVA, and continuous ePWV. Results In the overall cohort, all four variants were associated with EVA in the risk direction. rs5370 and rs72735260 remained significant after FDR correction. Each additional risk allele in the Total GRS increased the adjusted odds of EVA by 69% (OR 1.691, 95% CI 1.381–2.094), with a graded increase across genetic burden categories. Higher ENHO-GRS was associated with lower adropin, higher EDN1-GRS with higher endothelin-1, and higher Total GRS with greater AEI, which statistically mediated 51.8% of the GRS–EVA association. Within the study cohort, AEI discriminated EVA better than GRS (AUC 0.776 vs 0.661). Conclusions Combined ENHO – EDN1 genetic burden is associated with an adverse adropin–endothelin-1 balance and early vascular aging. Independent replication is required before clinical application.