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.