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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-GGG-M (52))
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Jaquish, Cashell E
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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Choi, Jihoon; Tantisira, Kelan G; Duan, Qing Ling (2018) Whole genome sequencing identifies high-impact variants in well-known pharmacogenomic genes. Pharmacogenomics J :
Empey, Philip E; Stevenson, James M; Tuteja, Sony et al. (2018) Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy. Clin Pharmacol Ther 104:664-674
Weitzel, Kristin W; Smith, D Max; Elsey, Amanda R et al. (2018) Implementation of Standardized Clinical Processes for TPMT Testing in a Diverse Multidisciplinary Population: Challenges and Lessons Learned. Clin Transl Sci 11:175-181
Cavallari, Larisa H; Lee, Craig R; Beitelshees, Amber L et al. (2018) Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. JACC Cardiovasc Interv 11:181-191
Smith, D Max; Weitzel, Kristin W; Cavallari, Larisa H et al. (2018) Clinical application of pharmacogenetics in pain management. Per Med 15:117-126
Bergmeijer, Thomas O; Reny, Jean-Luc; Pakyz, Ruth E et al. (2018) Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J 198:152-159
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
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
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

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