EDN1 and PHACTR1 variants and the NOS3-PHACTR1 interaction may shape susceptibility and severity in coronary artery disease.

Abstract

Coronary artery disease (CAD) is a complex disorder influenced by endothelial dysfunction, vascular inflammation, and thrombosis. This study evaluated selected genetic variants in endothelin signaling (EDN1, PHACTR1), nitric oxide metabolism (NOS3), and fibrinolysis (SERPINE1/PAI-1) in relation to CAD susceptibility, major clinical sub-phenotypes, and disease severity in a Turkish study population. A total of 1256 individuals who underwent coronary angiography were enrolled, including 748 CAD patients and 508 non-CAD controls. Genotyping of EDN1 rs3087459, PHACTR1 rs9349379, NOS3 rs1799983, and PAI-1 4G/5G variants were performed using quantitative real-time PCR. Logistic regression, haplotype, and gene-gene interaction analyses were conducted under multiple inheritance models. The EDN1 CC genotype was significantly associated with CAD (OR = 5.759, 95% CI: 1.319-25.149, p = 0.020), severe CAD (p = 0.012), and C allele with myocardial infarction (OR = 1.640, 95% CI: 1.091-2.465, p = 0.017) in males. Moreover, the PHACTR1 GG genotype was associated with premature CAD (OR = 1.721, 95%CI: 1.076-2.753, p = 0.024), and greater angiographic severity (p < 0.05). The NOS3 T allele carrier males had an increased risk for diabetes (OR = 1.449, 95%CI:1.057-1.985 p = 0.021), and CAD complexed with diabetes (CAD-DM) (OR = 1.619, 95%CI:1.004-2.610, p = 0.048). Notably, the interaction between NOS3 and PHACTR1 variants was consistently associated with CAD, severe CAD, premature CAD, and CAD-DM, and was further supported by higher stenosis severity indices and elevated troponin levels (p < 0.05). These findings demonstrate that variation within endothelial pathways extends beyond CAD susceptibility to shape angiographic complexity and clinical severity. Notably, a synergistic interaction between PHACTR1 and NOS3 modulates CAD related phenotypes, emphasizing that coordinated pathway disturbances contribute to CAD heterogeneity more than isolated variants.