Grant Detail

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Pharmacogenomics of Anti-platlet Intervention-2 (PAPI-2) Study

23 September 2005 - 30 June 2015
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

DESCRIPTION (provided by applicant): 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. 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.

10 Resulting Publications

• 1.

  2013

  Joshua P Lewis; Richard B Horenstein; Kathleen Ryan; Jeffrey R O'Connell; Quince Gibson; Braxton D Mitchell; Keith Tanner; Sumbul Chai; Kevin P Bliden; Udaya S Tantry; et al.

  The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

  Pharmacogenetics and genomics 2013;23(1):1-8.

• 2.

  2012

  J A Johnson; D M Roden; L J Lesko; E Ashley; T E Klein; A R Shuldiner

  Clopidogrel: a case for indication-specific pharmacogenetics.

  Clinical pharmacology and therapeutics 2012;91(5):774-6.

• 3.

  2012

  Stuart A Scott; Katrin Sangkuhl; Alan R Shuldiner; Jean-Sébastien Hulot; Caroline F Thorn; Russ B Altman; Teri E Klein

  PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19.

  Pharmacogenetics and genomics 2012;22(2):159-65.

• 4.

  2011

  J P Lewis; A S Fisch; K Ryan; J R O'Connell; Q Gibson; B D Mitchell; H Shen; K Tanner; R B Horenstein; R Pakzy; et al.

  Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response.

  Clinical pharmacology and therapeutics 2011;90(4):568-74.

• 5.

  2011

  J A Johnson; L H Cavallari; A L Beitelshees; J P Lewis; A R Shuldiner; D M Roden

  Pharmacogenomics: application to the management of cardiovascular disease.

  Clinical pharmacology and therapeutics 2011;90(4):519-31.

• 6.

  2011

  Amber L Beitelshees; David L Veenstra

  Evolving research and stakeholder perspectives on pharmacogenomics.

  JAMA : the journal of the American Medical Association 2011;306(11):1252-3.

• 7.

  2011

  Dan M Roden; Julie A Johnson; Stephen E Kimmel; Ronald M Krauss; Marisa Wong Medina; Alan Shuldiner; Russell A Wilke

  Cardiovascular pharmacogenomics.

  Circulation research 2011;109(7):807-20.

• 8.

  2011

  S A Scott; K Sangkuhl; E E Gardner; C M Stein; J-S Hulot; J A Johnson; D M Roden; T E Klein; A R Shuldiner;

  Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy.

  Clinical pharmacology and therapeutics 2011;90(2):328-32.

• 9.

  2011

  A L Beitelshees; R B Horenstein; M R Vesely; M R Mehra; A R Shuldiner

  Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions.

  Clinical pharmacology and therapeutics 2011;89(3):455-9.

• 10.

  2010

  Amber L Beitelshees

  Is ticagrelor the antiplatelet therapy panacea?

  Circulation. Cardiovascular genetics 2010;3(6):489-91.

Scientific Context

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