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Alan R. Shuldiner, MD; Jeffrey R. O’Connell, DPhil; Kevin P. Bliden, BS; Amish Gandhi, MD; Kathleen Ryan, MPH; Richard B. Horenstein, MD; Coleen M. Damcott, PhD; Ruth Pakyz, BS; Udaya S. Tantry, PhD; Quince Gibson, MBA; Toni I. Pollin, PhD; Wendy Post, MD, MS; Afshin Parsa, MD; Braxton D. Mitchell, PhD; Nauder Faraday, MD; William Herzog, MD; Paul A. Gurbel, MD

JAMA. 2009;302(8):849-857.

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 (h² = 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.

Author Affiliations: Division of Endocrinology, Diabetes and Nutrition, Department of Medicine (Drs Shuldiner, O’Connell, Gandhi, Horenstein, Damcott, Pollin, and Mitchell, Mss Ryan and Pakyz, and Mr Gibson) and Division of Nephrology, Department of Medicine (Dr Parsa), University of Maryland School of Medicine, Baltimore; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore (Dr Shuldiner); Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore (Mr Bliden and Drs Tantry, Herzog, and Gurbel); Division of Cardiology, Department of Medicine (Drs Post and Herzog); and Department of Anesthesiology and Critical Care Medicine (Dr Faraday), Johns Hopkins University School of Medicine, Baltimore.

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