PAPI-2 Profile

The Amish Pharmacogenomics of Anti-Platelet Intervention Study

Abstract (Reviewed, July 2010)

Anti-platelet therapy with clopidogrel (Plavix) and aspirin is the standard of care for secondary prevention of myocardial infarction. Despite its widespread use, 4 - 32% of individuals are not responsive to clopidogrel. This renewal application will build upon significant progress made during the initial funding period in which we completed the Amish Pharmacogenomics of Anti-platelet Intervention-1 (PAPI-1) Study. Through the first genome-wide association study (GWAS) of its kind, we found that the loss of function cytochrome P450 2C19*2 (CYP2C19*2) variant is a major determinant of clopidogrel response, accounting for 12% of the variation in response. In an independent cohort, we found that ~30% of the general population harboring CYP2C19*2 have poorer platelet response to clopidogrel and are at a 2.4-fold higher risk of having an ischemic cardiac event or death. The overall goal of this renewal application is to continue to advance the science of anti-platelet pharmacogenomics and its clinical translation. We hypothesize (a) CYP2C19 genotype-directed anti-platelet therapy will be superior to standard of care therapy; and (b) the genetic architecture of clopidogrel response includes common and rare variants in yet-to-be identified genes. We have amassed a team of multidisciplinary investigators and collaborators and will capitalize on synergies created by active participation in the Pharmacogenomics Research Network to address the following Specific Aims: (1) To conduct the PAPI-2 Study, a prospective multicenter randomized double-blind clinical trial comparing cardiovascular events using CYP2C19 genotype-directed versus standard of care anti-platelet therapy in over 2000 patients with coronary heart disease; (2) To identify common variants in novel genes and loci for clopidogrel response by performing a large GWAS as part of a new Clopidogrel Pharmacogenomics GWAS Consortium; and (3) To identify rare variants in genes previously not known to influence platelet function or clopidogrel response by performing genome-wide exon (exome) sequencing from the extremes of the distribution of clopidogrel response.

PAPI-2 Team

University of Maryland School of Medicine

University of Maryland School of Pharmacy Team

Johns Hopkins University School of Medicine Team

Sinai Hospital of Baltimore Team

Geisinger Health System Team

Christiana Care Health Services Team