Abstract
BACKGROUND: Dual antiplatelet therapy with aspirin and a P2Y₁₂ inhibitor is standard for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention. While ticagrelor offers superior efficacy in reducing ischemic events compared to clopidogrel, its use is limited by a higher incidence of dyspnea, an adverse reaction whose underlying predictors remain incompletely understood. Genetic variations in CYP3A4/5, the principal enzymes responsible for ticagrelor metabolism, may influence interindividual susceptibility to this side effect. METHODS: In a prospective cohort of 385 ACS patients on ticagrelor, we genotyped CYP3A4 rs2242480 and CYP3A5 rs776746. Outcomes (dyspnea per CTCAE v5.0, bleeding per BARC criteria) were assessed over 1 year. Associations were analyzed using logistic regression and GMDR modeling. RESULTS: The CYP3A5 rs776746 genotype strongly predicted dyspnea risk. Compared to the CC genotype, CT and TT genotypes were associated with a 55% and 91% reduced risk, respectively. Carriers of the combined CT/TT genotypes had a 63% lower risk. CC genotype carriers (poor metabolizers) exhibited a 2.3-fold higher dyspnea incidence. No significant associations were found for CYP3A4 rs2242480 or for bleeding outcomes. CONCLUSION: The CYP3A5 rs776746 CC genotype is a significant genetic biomarker for ticagrelor-induced dyspnea. Pre-emptive genotyping could enable personalized antiplatelet therapy, such as alternative P2Y₁₂ inhibitors for high-risk CC carriers, to improve patient safety.