OBJECTIVES: This study sought to evaluate the influence of single nucleotide 
polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose 
clopidogrel after percutaneous coronary intervention (PCI).
BACKGROUND: There is a lack of prospective, multicenter data regarding the 
effect of different genetic variants on clopidogrel pharmacodynamics over time 
in patients undergoing PCI.
METHODS: The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on 
Thrombosis And Safety) trial screened patients with platelet function testing 
after PCI and randomly assigned those with high on-treatment reactivity (OTR) to 
either high- or standard-dose clopidogrel; a cohort of patients without high OTR 
were also followed. DNA samples obtained from 1,028 patients were genotyped for 
41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical 
characteristics, the associations between the SNPs and OTR using linear 
regression were evaluated.
RESULTS: CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 
0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months 
after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and 
other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 
alleles were significantly more likely to display persistently high OTR at 30 
days and 6 months, irrespective of treatment assignment. The portion of the risk 
of persistently high OTR at 30 days attributable to reduced-function CYP2C19 
allele carriage was 5.2% in the patients randomly assigned to high-dose 
clopidogrel.
CONCLUSIONS: CYP2C19, but not PON1 or ABCB1, is a significant determinant of the 
pharmacodynamic effects of clopidogrel, both early and late after PCI. In 
patients with high OTR identified by platelet function testing, the CYP2C19 
genotype provides limited incremental information regarding the risk of 
persistently high reactivity with clopidogrel 150-mg maintenance dosing. 
(Genotype Information and Functional Testing Study [GIFT]; NCT00992420).