AdvisorShuldiner, Alan R.
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AbstractCoronary artery disease is a leading cause of death in the United States, and patients who develop acute coronary syndrome undergo vessel revascularization, which commonly involves percutaneous coronary intervention with dual-antiplatelet therapy, including clopidogrel and aspirin. Patient variability in both drugs is well-established. Our genome-wide association study (GWAS) in the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study yielded significant associations between CYP2C19*2 (rs4244285) and clopidogrel response and between PEAR1 rs12041331 and aspirin response. Given our heritability estimates, we hypothesized that other important pharmacogenetic variants remain unidentified. To test this hypothesis, we explored the impact of 1936 variants in 231 genes on clopidogrel response using the Drug Metabolizing Enzymes and Transporters (DMET) array. In addition to confirming the association with CYP2C19*2 (P = 5.34 x 10-13), we observed a novel association between clopidogrel response and the rs11249454 variant in UDP glucuronosyltransferase 2A1 and 2A2 (UGT2A1/2; P = 2.92 x 10-5). Specifically, this variant influenced clopidogrel response in a sex-specific manner, with significance in women (P = 8.40 x 10-6), but not in men (P = 0.21). Additionally, given the association between PEAR1 rs12041331 and aspirin response in the PAPI Study, we used computational methodologies to predict genes, phenotypes, and diseases related to PEAR1 expression using data from ~75,000 publicly available microarrays. Meta-analysis of microarray data suggested that PEAR1 may significantly impact endothelial cell biology. To confirm these results, we functionally validated the impact of PEAR1 rs12041331 on endothelial cell migration distance in primary human umbilical vein endothelial cells using an ex vivo migration assay (P = 0.04). Finally, we confirmed the impact of this variant on endothelial function clinically through assessment of in vivo flow-mediated dilation of the brachial artery in 641 participants of the Heredity and Phenotype Intervention (HAPI) Heart Study (P = 0.02). Taken together, the results of these studies highlight a novel variant in clopidogrel response and a novel biological mechanism of an aspirin response gene. These studies provide the framework for future investigations to better understand how UGT2A1/2 and endothelial PEAR1 affect clopidogrel and aspirin response, respectively.
DescriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2015
Platelet Aggregation Inhibitors