Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

Abstract

Rolf P Kreutz,1,2 Janelle Owens,2 Yan Jin,2 Perry Nystrom,2 Zeruesenay Desta,2 Yvonne Kreutz,2 Jeffrey A Breall,1 Lang Li,3 ChienWei Chiang,3 Richard J Kovacs,1 David A Flockhart21Krannert Institute of Cardiology, 2Division of Clinical Pharmacology, Indiana University School of Medicine, 3Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USAAbstract: Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 µM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.Keywords: clopidogrel, pharmacogenetics, CYP450, platelet aggregation