PROJECT SUMMARY Clopidogrel as well as other P2Y12 receptor inhibitors are commonly prescribed to prevent recurrent thrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Variability in in response to these medications is well-established and contributes to increased risk of experiencing a cardiovascular event when high platelet reactivity persists or in pathological bleeding when on-treatment platelet aggregation is too low. While substantial effort has been made to identify the determinants of clopidogrel response, much of the variability still remains unaccounted for. In this application, we utilize novel methodologies and analytical strategies to identify unknown biomarkers that impact clopidogrel efficacy. In Specific Aim 1, we integrate pharmacogenomic data, deep metabolomic profiling, clopidogrel pharmacokinetic assessment, and extensive platelet-based phenotyping in participants of the Pharmacogenomics of Anti- Platelet Intervention (PAPI) Study to unveil new insights into the mechanisms of variable drug action and response. Specifically, in 599 PAPI participants, we will perform genome-wide association studies pre- and post-clopidogrel intervention (75mg/d for 7d) for platelet aggregation, parent prodrug and clopidogrel active metabolite concentrations, and approximately 1,000 metabolites measured through metabolomic profiling. These data will be used to perform informed pathway/network analysis, Mendelian randomization, and Bayesian colocalization to better understand multiomic signatures of clopidogrel exposure and response and to build metabolomics-informed polygenic risk scores (miPRS) for prediction of low and high on-treatment platelet aggregation. In Specific Aim 2, we extend these findings in over 2,800 patients with cardiovascular disease recruited into the International Clopidogrel Pharmacogenomics Consortium (ICPC). In this large clinical investigation of antiplatelet therapy, we will attempt to replicate significant single-SNP associations with platelet aggregation as well as assess potential impact on recurrent cardiovascular event risk. Moreover, we will deploy miPRSs developed in the PAPI Study and compare this instrument to previously published risk scores with respect to platelet reactivity and major adverse cardiovascular outcomes including myocardial infarction, stroke, and cardiovascular-related death. To date, no investigation has systematically evaluated the metabolic consequences of clopidogrel exposure nor utilized pharmacometabolomic strategies to better understand variable antiplatelet efficacy or response prediction. We anticipate that the completion of the research proposed in this application will enhance precision medicine efforts through identification of novel multiomic signatures and biomarkers that predict response to clopidogrel therapy and will establish clinical strategies aimed at defining optimal personalized treatment plans to reduce adverse clinical outcomes in those with increased recurrent cardiovascular event risk.

PROJECT NARRATIVE Clopidogrel is among the most widely prescribed medications to prevent adverse cardiovascular outcomes in patients with acute coronary syndrome and/or undergoing percutaneous coronary intervention. Given the wide variability in platelet aggregation and clinical outcomes in response to clopidogrel therapy, it is critical to identify the metabolic and genetic factors that cause altered drug efficacy and to better predict those who are more susceptible to altered clopidogrel response. The proposed research will provide insights into the cause(s) of clopidogrel failure and will ultimately help physicians prescribe the most effective antiplatelet therapy based on metabolic and genetic background.