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.