Prostaglandin-Endoperoxide Synthase 1 Regulatory Variants Link Aspirin-Treated Cardiovascular Outcomes to Multicellular Cyclooxygenase-1 Expression and Activity Beyond Platelet-Derived Cyclooxygenase-1 Inhibition

BACKGROUND: Prostaglandin-endoperoxide synthase 1 (PTGS1) encodes cyclooxygenase-1 (COX-1). METHODS: In total, 486 cardiovascular patients, 454 on mono-antiplatelet therapy (MAPT), 32 on dual antiplatelet therapy (DAPT, aspirin plus clopidogrel), had complete data including COX-1-specific platelet function and median 4.75-year follow-up. MACE comprised acute myocardial infarction, acute stroke, and ischemia-driven revascularization. Eighteen bioinformatically annotated PTGS1 regulatory variants were genotyped. RESULTS: Smoking and clopidogrel exposure significantly modified LAR. Kaplan-Meier analysis linked LAR to higher crude MACE odds in MAPT and MAPT+DAPT groups (log-rank P < 0.05). Genetic analyses clarified gene-LAR, gene-MACE, gene-LAR-MACE interrelationships. Promoter rs1330344 showed lower LAR odds, with unchanged MACE odds, consistent with mild COX-1 modulation. Intronic rs7866582 conferred higher MACE odds alone, consistent with leukocyte COX-1/proinflammatory prostaglandin elevation. 3'-untranslated region (3'-UTR) rs10306190 exhibited marginally higher LAR odds yet lower MACE odds, consistent with variant-mediated COX-1 upregulation and marked vascular COX-1/PGI CONCLUSIONS: LAR and PTGS1 variants lack population-level value for MACE prediction. This study links aspirin-treated MACE to multicellular COX-1 actions beyond platelets.