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, Toni I. Pollin, Wendy S Post, Afshin Parsa, Braxton D. Mitchell, Nauder Faraday, William Raymond Herzog, Paul A. Gurbel

Research output: Contribution to journalArticle

Abstract

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-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.

Original languageEnglish (US)
Pages (from-to)849-858
Number of pages10
JournalJournal of the American Medical Association
Volume302
Issue number8
DOIs
StatePublished - Aug 26 2009

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clopidogrel
Cytochrome P-450 Enzyme System
Genotype
Blood Platelets
Platelet Aggregation
Adenosine Diphosphate
Pharmacogenetics
Percutaneous Coronary Intervention
Therapeutics
Amish
Genome-Wide Association Study
Linkage Disequilibrium
Platelet Activation
Acute Coronary Syndrome

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shuldiner, A. R., O'Connell, J. R., Bliden, K. P., Gandhi, A., Ryan, K., Horenstein, R. B., ... Gurbel, P. A. (2009). Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. Journal of the American Medical Association, 302(8), 849-858. https://doi.org/10.1001/jama.2009.1232

Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. / Shuldiner, Alan R.; O'Connell, Jeffrey R.; Bliden, Kevin P.; Gandhi, Amish; Ryan, Kathleen; Horenstein, Richard B.; Damcott, Coleen M.; Pakyz, Ruth; Tantry, Udaya S.; Gibson, Quince; Pollin, Toni I.; Post, Wendy S; Parsa, Afshin; Mitchell, Braxton D.; Faraday, Nauder; Herzog, William Raymond; Gurbel, Paul A.

In: Journal of the American Medical Association, Vol. 302, No. 8, 26.08.2009, p. 849-858.

Research output: Contribution to journalArticle

Shuldiner, AR, O'Connell, JR, Bliden, KP, Gandhi, A, Ryan, K, Horenstein, RB, Damcott, CM, Pakyz, R, Tantry, US, Gibson, Q, Pollin, TI, Post, WS, Parsa, A, Mitchell, BD, Faraday, N, Herzog, WR & Gurbel, PA 2009, 'Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy', Journal of the American Medical Association, vol. 302, no. 8, pp. 849-858. https://doi.org/10.1001/jama.2009.1232
Shuldiner, Alan R. ; O'Connell, Jeffrey R. ; Bliden, Kevin P. ; Gandhi, Amish ; Ryan, Kathleen ; Horenstein, Richard B. ; Damcott, Coleen M. ; Pakyz, Ruth ; Tantry, Udaya S. ; Gibson, Quince ; Pollin, Toni I. ; Post, Wendy S ; Parsa, Afshin ; Mitchell, Braxton D. ; Faraday, Nauder ; Herzog, William Raymond ; Gurbel, Paul A. / Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. In: Journal of the American Medical Association. 2009 ; Vol. 302, No. 8. pp. 849-858.
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abstract = "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-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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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 S

AU - Parsa, Afshin

AU - Mitchell, Braxton D.

AU - Faraday, Nauder

AU - Herzog, William Raymond

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-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-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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