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


METHODS
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.


METHODS
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).


CONCLUSIONS
CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.
Shuldiner
Alan R
AR
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
O'Connell
Jeffrey R
JR
Bliden
Kevin P
KP
Gandhi
Amish
A
Ryan
Kathleen
K
Horenstein
Richard B
RB
Damcott
Coleen M
CM
Pakyz
Ruth
R
Tantry
Udaya S
US
Gibson
Quince
Q
Pollin
Toni I
TI
Post
Wendy
W
Parsa
Afshin
A
Mitchell
Braxton D
BD
Faraday
Nauder
N
Herzog
William
W
Gurbel
Paul A
PA
D000328:Adult; D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10; D002986:Clinical Trials as Topic; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000235:genetics* / Q000628:therapy; D065731:Cytochrome P-450 CYP2C19; D005006:Ethnicity / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
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