CYP2C19 genetic variants and coronary atherosclerosis: insights beyond antiplatelet therapy

Abstract Background The CYP2C19 gene encodes a key enzyme involved in drug metabolism, particularly influencing antiplatelet therapy response in patients with acute coronary syndrome (ACS). Beyond its pharmacogenetic role, studies have indicated that CYP2C19 loss-of-function variants may play a role as risk factors for premature cerebral infarction and multi-site atherosclerosis. However, the extent to which CYP2C19 polymorphisms influence coronary artery disease (CAD) severity remains unclear. Methods We analyzed 182 ACS patients (2020–2024) who underwent CYP2C19 genotyping. Patients were classified as Normal Metabolizers (NM, *1/*1), Gain-of-Function (GOF, *1/*17, *17/*17), and Loss-of-Function (LOF, *1/*2, *2/*2). Allele frequencies in our cohort were 54.4% for *1 (wild type), 27.5% for *17 (GOF), and 18.1% for *2 (LOF). Clinical and procedural characteristics, including number of diseased vessels, presence of chronic total occlusion (CTO), history of previous PCI, ejection fraction (LVEF), and troponin peak, were compared across genotypic groups. Logistic regression adjusted for clinical confounders assessed independent associations. None of the patients enrolled in the study were on clopidogrel therapy at enrollment. Results Compared to the general European population, our cohort featured a higher prevalence of LOF alleles, which may reflect a genetic predisposition influencing CAD risk. At univariable analysis, CYP2C19 LOF carriers had a significantly higher prevalence of CTO at coronary angiography (OR = 2.25, 95% CI: 1.15–4.42, p = 0.018), multivessel disease (OR = 1.85, 95% CI: 0.98–3.45, p = 0.057), and history of previous PCI (OR = 2.10, 95% CI: 1.10–4.00, p = 0.026). After adjusting for age, body mass index (BMI), diabetes, hypertension, smoking, and estimated glomerular filtration rate (eGFR by CKD-EPI formula), multivariable analysis, LOF genotype remained an independent predictor of presence of a CTO (OR = 2.05, 95% CI: 1.05–4.01, p = 0.034) and history of previous PCI (OR = 1.95, 95% CI: 1.02–3.90, p = 0.042), while the association with multivessel disease was no longer statistically significant (OR = 1.75, 95% CI: 0.90–3.30, p = 0.075). No significant differences were observed for LVEF or troponin peak. Conclusion Our findings suggest that CYP2C19 LOF polymorphisms are independently associated with a higher prevalence of chronic total occlusion and recurrent need for percutaneous coronary intervention, indicating a potential role in atherosclerosis progression beyond antiplatelet therapy. However, the cross-sectional nature of this study limits the ability to establish causality. Longitudinal studies with follow-up are needed to evaluate the impact of CYP2C19 polymorphisms on CAD progression and clinical outcomes over time, further clarifying their role in risk stratification and therapeutic decision-making.