Impact of genetic variants on post-clopidogrel platelet reactivity in patients after elective percutaneous coronary intervention

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; (star)2, (star)3) and gain-of-function (GOF; (star)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 mu M > 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 ana-lysis, 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. Original submitted 28 February 2011; Revision submitted 5 May 2011