TY - JOUR
T1 - Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy
AU - Shuldiner, Alan R.
AU - O'Connell, Jeffrey R.
AU - Bliden, Kevin P.
AU - Gandhi, Amish
AU - Ryan, Kathleen
AU - Horenstein, Richard B.
AU - Damcott, Coleen M.
AU - Pakyz, Ruth
AU - Tantry, Udaya S.
AU - Gibson, Quince
AU - Pollin, Toni I.
AU - Post, Wendy
AU - Parsa, Afshin
AU - Mitchell, Braxton D.
AU - Faraday, Nauder
AU - Herzog, William
AU - Gurbel, Paul A.
PY - 2009/8/26
Y1 - 2009/8/26
N2 - 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-offunction 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 × 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 × 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.
AB - 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-offunction 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 × 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 × 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.
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U2 - 10.1001/jama.2009.1232
DO - 10.1001/jama.2009.1232
M3 - Article
C2 - 19706858
AN - SCOPUS:69249219296
SN - 0098-7484
VL - 302
SP - 849
EP - 858
JO - JAMA
JF - JAMA
IS - 8
ER -