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 lnterventlon-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 Alms: (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.

Public Health Relevance

The proposed randomized clinical trial will provide the evidence base for translation of genotype-directed anti-platelet therapy into clinical practice. The Identification of common and rare variants in novel genes for clopidogrel response will provide new insights into platelet biology and variation in anti-platelet therapy response, and potentially, new targets for more effective agents to prevent and treat CHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL105198-07
Application #
8139037
Study Section
Special Emphasis Panel (ZRG1-GGG-M (52))
Program Officer
Paltoo, Dina
Project Start
2005-09-23
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2011
Total Cost
$2,293,673
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Luzum, J A; Pakyz, R E; Elsey, A R et al. (2017) The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems. Clin Pharmacol Ther 102:502-510
Tise, Christina G; Anforth, Leslie E; Zhou, Albert E et al. (2017) Sex-specific effects of serum sulfate level and SLC13A1 nonsense variants on DHEA homeostasis. Mol Genet Metab Rep 10:84-91
Cavallari, L H; Beitelshees, A L; Blake, K V et al. (2017) The IGNITE Pharmacogenetics Working Group: An Opportunity for Building Evidence with Pharmacogenetic Implementation in a Real-World Setting. Clin Transl Sci 10:143-146
Johnson, J A; Caudle, K E; Gong, L et al. (2017) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther 102:397-404
Sweet, K; Sturm, A C; Schmidlen, T et al. (2017) EMR documentation of physician-patient communication following genomic counseling for actionable complex disease and pharmacogenomic results. Clin Genet 91:545-556
Backman, Joshua D; O'Connell, Jeffrey R; Tanner, Keith et al. (2017) Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response. Pharmacogenet Genomics 27:159-163
Empey, Philip E; Stevenson, James M; Tuteja, Sony et al. (2017) Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy. Clin Pharmacol Ther :
Cavallari, Larisa H; Weitzel, Kristin W; Elsey, Amanda R et al. (2017) Institutional profile: University of Florida Health Personalized Medicine Program. Pharmacogenomics 18:421-426
O'Donnell, P H; Wadhwa, N; Danahey, K et al. (2017) Pharmacogenomics-Based Point-of-Care Clinical Decision Support Significantly Alters Drug Prescribing. Clin Pharmacol Ther 102:859-869
Peterson, J F; Field, J R; Shi, Y et al. (2016) Attitudes of clinicians following large-scale pharmacogenomics implementation. Pharmacogenomics J 16:393-8

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