Sex Differences in Clopidogrel Effects Among Young Patients With Acute Coronary Syndrome: A Role for Genetics?
Amanpreet Kaur1, Rachel P Dreyer2,3, Thomas W Marsh4,5
1Centre for Outcomes Research and Evaluation, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.
Insights
Young women with acute coronary syndrome face worse outcomes due to clopidogrel, potentially linked to sex-gene interactions. This study found female carriers of CYP2C9*3 had a higher risk of atherothrombotic events.
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Genetics
Background:
- Young women with acute coronary syndrome (ACS) experience poorer health outcomes compared to men.
- Sex differences in antiplatelet agent efficacy, like clopidogrel, may contribute to these disparities.
- Genetic variations in drug-metabolizing enzymes (cytochrome P450 [CYP] family) influence clopidogrel response, but sex-specific genetic impacts are underexplored.
Purpose of the Study:
- To investigate potential interactions between sex and CYP gene variants in clopidogrel users.
- To determine if these sex-by-gene interactions impact 1-year adverse clinical outcomes in ACS patients.
Main Methods:
- Analysis of a combined cohort of 2272 ACS patients (56% female).
- Examination of sex and CYP variant interactions among clopidogrel users at admission and discharge.
- Assessment of associations with 1-year readmission due to cardiac events.
Main Results:
- In a case-only analysis, female carriers of the CYP2C9*3 loss-of-function allele had a significantly higher risk of atherothrombotic events (OR=3.77).
- Multivariable analysis of clopidogrel users at discharge (n=1733) revealed women had a higher risk of 1-year atherothrombotic readmissions (OR=1.55).
- No significant association was found between loss-of-function CYP alleles and 1-year readmissions individually or via a genetic risk score.
Conclusions:
- Sex-by-gene interactions may play a role in the observed sex differences in clopidogrel's efficacy and clinical outcomes.
- Further research is needed to understand these interactions for personalized antiplatelet therapy in ACS.
- Improved understanding of sex-by-gene interactions is crucial for addressing sex disparities in drug metabolism and treatment response.
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.
Related Concept Videos
01:20Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
01:30Acute Coronary Syndrome III: Diagnostic Studies
01:19Acute Coronary Syndrome II: Pathophysiology and Clinical Manifestations
01:21Factors Affecting Drug Response: Overview
01:29Factors Affecting Protein-Drug Binding: Patient-Related Factors
Age stands as a key determinant in protein-drug binding. Neonates, characterized by low albumin content, experience heightened concentrations of unbound drugs such as phenytoin and...
01:19Factors Affecting Drug Biotransformation: Biological
Species differences: Variations in enzyme systems across species can cause disparities in drug metabolism. For instance, humans may metabolize certain drugs faster than rodents, altering therapeutic effects.
Strain differences: Genetic variations within a species can result in differing enzyme activity, impacting drug response and toxicity. For example, some mouse strains may...