Project Summary Pharmacogenomics has shown itself to be on the leading edge of clinical translatability in genomic medicine, with findings that are currently implemented across the US and internationally. Clopidogrel is an oral prodrug used to treat coronary artery disease. Several pharmacogenomic studies have consistently shown that single nucleotide polymorphisms (SNPs) in CYP2C19 are associated with clopidogrel efficacy and adverse events. No study has comprehensively studied the transcriptomic and epigenomic associations to clopidogrel response outside of European populations, with no studies in admixed populations. Thus, the ability of non-European populations to benefit equitably from those pharmacogenomic findings in clopidogrel is unknown. We propose a study of clopidogrel response in admixed Caribbean Hispanics. Our preliminary data shows that local ancestry is an important consideration in understanding genomic associations to clopidogrel response, gene expression and predictive modeling in admixed populations. We have also included a study of SDoH within this study population to assess how social factors may impact overall healthcare in this understudied population. We have assembled a team with long-standing expertise in patient recruitment and engagement in Puerto Rico, public health, pharmacogenomics, and genomic methods in admixed populations to accomplish 3 aims: AIM1: Creation of a multi-omic dataset and predictors of clopidogrel response in PR. We will collect biospecimens for all 3 omics data types (genomics, transcriptomics and epigenomics) in 200 participants at two time points (prior to clopidogrel dosing and after 1 month of therapy), and from 200 healthy controls. We will measure P2Y12 Reactivity Units at each time point and will follow all participants for 1 year to identify adverse events. We will compare differences in the transcriptome (platelet) and the DNA methylome for association to clopidogrel response at each time point. AIM2: We will use both the Social Vulnerability Metric (SVM), a composite measure of SDoH variables, and the CAT-SDoH, a computer adaptive personal assessment tool, to evaluate how social vulnerability may impact the outcomes of clopidogrel drug therapy. AIM3: We will develop a platelet gene expression prediction model using our LA-GEM methodology using healthy Caribbean Hispanic controls and then conduct a TWAS on our Caribbean Hispanic clopidogrel cohort. Our proposed work will bring equity to the pharmacogenomics of clopidogrel in this understudied population.