AIM: To determine the effect of various SNPs on post-clopidogrel platelet 
reactivity and clinical outcome.
MATERIALS & METHODS: Cytochrome 2C19 (CYP2C19) loss-of-function (LOF; *2, *3) 
and gain-of-function (GOF; *17) allelic variants, together with ABCB1 (3435 C→T 
and 2677 G→T/A) and paraoxonase-1 (PON-1; 192 Q→R) SNPs were analyzed in 189 
patients after elective stent implantation who participated in a randomized, 
placebo-controlled trial (NCT00638326). Platelet reactivity was determined with 
light transmission aggregometry and vasodilator stimulated phosphoprotein 
phosphorylation (VASP-PRI) 12-24 h after 600 mg clopidogrel. High on-treatment 
platelet reactivity (HTPR) was defined according to the consensus definition 
(ADP 5 µM >46%; VASP-PRI>50%).
RESULTS: In the case of CYP2C19 genotypes, a gene-dose effect was observed in 
ADP reactivity with the lowest values in GOF homozygotes and the highest degree 
in patients carrying two LOF alleles. The odds for HTPR also increased with the 
number of LOF alleles. There were no significant differences in platelet 
reactivity according to PON-1 or ABCB1 genotypes. In multivariate analysis, the 
presence of a CYP2C19 LOF allele turned out to be the independent determinant of 
HTPR. Although the study was not powered to clinical outcome (not LOF 
heterozygotes), only patients with two LOF alleles had a significantly higher 
risk for cardiovascular death, myocardial infarction or unplanned target vessel 
revascularization at 1 year compared with non-LOF carriers.
CONCLUSION: Genetic variants in CYP2C19 have a gene-dose effect on 
post-clopidogrel platelet reactivity, with homozygote LOF carriers having the 
highest risk for HTPR and for adverse ischemic events. Neither ABCB1 nor PON-1 
genotypes significantly influenced platelet reactivity or outcome.