Publication Detail

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Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.

Alan R Shuldiner; Jeffrey R O'Connell; Kevin P Bliden; Amish Gandhi; Kathleen Ryan; Richard B Horenstein; Coleen M Damcott; Ruth Pakyz; Udaya S Tantry; Quince Gibson; et al. (Profiled Authors: Coleen M Damcott; Richard B Horenstein; Braxton D Mitchell Jr.; Jeffrey R O'Connell; Afshin Parsa; Toni I Pollin; Alan R Shuldiner)

Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 W Redwood St, Room 494, Baltimore, MD 21201, USA. ashuldin@medicine.umaryland.edu
JAMA : the journal of the American Medical Association 2009;302(8):849-57.

CONTEXT: Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)-dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events. OBJECTIVE: To identify gene variants that influence clopidogrel response. DESIGN, SETTING, AND PARTICIPANTS: In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention. MAIN OUTCOME MEASURE: ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events. RESULTS: Platelet response to clopidogrel was highly heritable (h(2) = 0.73; P < .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10(-13) for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10(-11)). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02). CONCLUSION: CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.

3 Originating Grant

• 1.

  Shuldiner, Alan R

  Pharmacogenomics of CVD risk Reduction

  23 September 2005 - 31 August 2010

  NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

• 2.

  SHULDINER, ALAN R.

  Mid-Atlantic Nutrition Obesity Research Center

  15 September 2005 - 31 August 2015

  NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

• 3.

  Reece, E Albert

  General Clinical Research Center

  1 March 2002 - 30 June 2010

  NATIONAL CENTER FOR RESEARCH RESOURCES

Scientific Context

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