BACKGROUND Variations of genes encoding cytochrome enzymes, drug transporters, and paraoxonase have recently been reported to be associated with clopidogrel response variability besides the well-known CYP2C19 loss-of-function (LOF) alleles. We determined whether newly reported genetic variations are associated with clopidogrel on-treatment platelet reactivity (OPR) in Korean patients.

METHODS OPR was measured in 1264 consecutive patients who underwent percutaneous coronary intervention using the VerifyNowP2Y12 assay system and genotyping of PON-1 Q192R, ABCB1 C3435T, CYP1A2*1F, CYP2B6*6, CYP2C19*2, CYP2C19*3, CYP2C19*17, CYP3A4 (IVS10+12G>A), and CYP3A5*3 was performed. We applied two different cutoffs, i.e. 240 P2Y12 reaction units (PRU) and 253 PRU, to define high OPR.

RESULTS Mean OPR of the entire population was 231±83 PRU. Genetic variations of ABCB1 and PON-1 genes as well as that of CYP1A2, 2B6, 3A4, and 3A5 were not associated with clopidogrel response variability. As for CYP2C19, patients were classified into 4 metabolism genotypes: 0.6% ultrarapid (UM), 40.3% extensive (EM), 48.8% intermediate (IM), and 10.3% poor metabolizers (PM). After adjustment for possible confounders, CYP2C19 metabolism genotype was associated with a significant increase in OPR: effect on OPR-difference: +27 PRU, p=0.015 for EM, +53 PRU, p<0.001 for IM, and +74 PRU, p=0.006 for PM compared with UM. In multivariable analysis, the CYP2C19 genotype was the only independent predictor of high-OPR among genetic variations using two different cutoffs.

CONCLUSIONS Among genes postulated to be involved in clopidogrel metabolism, only the CYP2C19 genotype is associated with response variability and emerged as an independent predictor of high-OPR using two different cutoffs. PON-1 and ABCB1 genetic variants do not affect clopidogrel OPR in Korean patients.