Sex Differences in Clopidogrel Effects Among Young Patients With Acute Coronary Syndrome: A Role for Genetics?

Background: Poorer health outcomes experienced by young women with acute coronary syndrome may be related to sex differences in the safety and efficacy of antiplatelet agents, such as clopidogrel. Polymorphisms in drug metabolism enzyme (cytochrome P450 [CYP] family) genes are independent factors for the variability in response to clopidogrel. However, a sex-specific impact of genetics to explain worse clinical outcomes in women has not been explored extensively. Therefore, our objective was to determine whether an interaction of sex with CYP variants occurs among users of clopidogrel, and if so, its impact on 1-year adverse clinical outcomes. Methods: We used data from a combined cohort of 2272 patients (median age 49 years; 56% female) hospitalized for acute coronary syndrome. We examined interactions between sex and CYP variants among clopidogrel users at admission and discharge to assess associations with 1-year readmission due to cardiac events. Results: The case-only analysis of 177 participants on clopidogrel at the time of presentation showed that the risk of an atherothrombotic event was greater in female carriers of the CYP2C9*3 loss-of-function allele (odds ratio = 3.77, 95% confidence interval = 1.54-9.24). The results of the multivariable logistic regression model for users of clopidogrel at discharge (n = 1733) indicated that women had significantly higher risk of atherothrombotic readmissions at 1 year (odds ratio = 1.55, 95% confidence interval = 1.16-2.07), compared to the risk for men, but the loss-of-function alleles, either individually or through a genetic risk score, were not associated with 1-year readmissions. Conclusion: This study highlights the need for an improved understanding of the role of sex-by-gene interactions in causing sex differences in drug metabolism.