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

Aybike Sena Ozuynuk-Ertugrul¹, Berkay Ekici², Ajar Kocak²

¹Istanbul University, Aziz Sancar Institute of Experimental Medicine, Department of Genetics, Istanbul, Turkey.

Clinica Chimica Acta; International Journal of Clinical Chemistry

|August 22, 2026

Insights

Genetic variants in endothelin (EDN1) and PH domain-containing protein 1 (PHACTR1) are linked to coronary artery disease (CAD) susceptibility and severity. A synergistic interaction between PHACTR1 and nitric oxide synthase 3 (NOS3) significantly modulates CAD phenotypes.

Area of Science:

Cardiovascular Genetics
Molecular Cardiology
Genetics of Atherosclerosis

Background:

Coronary artery disease (CAD) pathogenesis involves endothelial dysfunction, inflammation, and thrombosis.
Genetic factors play a crucial role in the susceptibility and progression of CAD.
Endothelial signaling pathways, including endothelin, nitric oxide, and fibrinolysis, are implicated in cardiovascular health.

Purpose of the Study:

To investigate the association of genetic variants in EDN1, PHACTR1, NOS3, and SERPINE1/PAI-1 with CAD.
To evaluate the relationship between these genetic variants and clinical CAD sub-phenotypes, including disease severity and premature onset.
To explore potential gene-gene interactions influencing CAD risk and clinical presentation.

Main Methods:

A case-control study involving 1256 individuals (748 CAD patients, 508 controls) undergoing coronary angiography.
Genotyping of specific variants (EDN1 rs3087459, PHACTR1 rs9349379, NOS3 rs1799983, PAI-1 4G/5G) using quantitative real-time PCR.
Statistical analyses including logistic regression, haplotype analysis, and gene-gene interaction models were employed.

Main Results:

The EDN1 CC genotype was associated with increased CAD risk and severity, while the C allele correlated with myocardial infarction in males.
PHACTR1 GG genotype was linked to premature CAD and greater angiographic severity.
NOS3 T allele carriers showed increased risk for diabetes and CAD with diabetes (CAD-DM), particularly in males.
A significant synergistic interaction between NOS3 and PHACTR1 variants was observed across multiple CAD phenotypes, including severity and diabetes comorbidity.

Conclusions:

Genetic variations in endothelial pathway genes contribute to CAD susceptibility and clinical heterogeneity.
The PHACTR1 and NOS3 gene variants exhibit a synergistic interaction, significantly influencing CAD phenotypes beyond individual effects.
These findings highlight the importance of coordinated pathway disturbances in understanding CAD complexity and severity.

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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.

Keywords:

Coronary artery disease EDN1 Myocardial Infarction NOS3 PHACTR1 Single nucleotide polymorphism

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