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

Publication ,  Journal Article
Shuldiner, AR; O'Connell, JR; Bliden, KP; Gandhi, A; Ryan, K; Horenstein, RB; Damcott, CM; Pakyz, R; Tantry, US; Gibson, Q; Pollin, TI ...
Published in: JAMA
August 26, 2009

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.

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Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

August 26, 2009

Volume

302

Issue

8

Start / End Page

849 / 857

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Ticlopidine
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Platelet Aggregation
  • Pharmacogenetics
  • Middle Aged
  • Male
  • Humans
  • Genotype
 

Citation

APA
Chicago
ICMJE
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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. JAMA, 302(8), 849–857. https://doi.org/10.1001/jama.2009.1232
Shuldiner, Alan R., Jeffrey R. O’Connell, Kevin P. Bliden, Amish Gandhi, Kathleen Ryan, Richard B. Horenstein, Coleen M. Damcott, et al. “Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.JAMA 302, no. 8 (August 26, 2009): 849–57. https://doi.org/10.1001/jama.2009.1232.
Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849–57.
Shuldiner, Alan R., et al. “Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.JAMA, vol. 302, no. 8, Aug. 2009, pp. 849–57. Pubmed, doi:10.1001/jama.2009.1232.
Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009 Aug 26;302(8):849–857.
Journal cover image

Published In

JAMA

DOI

EISSN

1538-3598

Publication Date

August 26, 2009

Volume

302

Issue

8

Start / End Page

849 / 857

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Ticlopidine
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Platelet Aggregation
  • Pharmacogenetics
  • Middle Aged
  • Male
  • Humans
  • Genotype