title: Genetic determinants of clopidogrel responsiveness in Koreans treated with drug-eluting stents.
abstract: 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.
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jin Joo
authors.initials: JJ
authors.lastname: Park
authors.forename: Kyung Woo
authors.initials: KW
authors.lastname: Park
authors.forename: Jeehoon
authors.initials: J
authors.lastname: Kang
authors.forename: Ki-Hyun
authors.initials: KH
authors.lastname: Jeon
authors.forename: Si-Hyuck
authors.initials: SH
authors.lastname: Kang
authors.forename: Hyo Suk
authors.initials: HS
authors.lastname: Ahn
authors.forename: Jung-Kyu
authors.initials: JK
authors.lastname: Han
authors.forename: Jin-Sin
authors.initials: JS
authors.lastname: Koh
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Han-Mo
authors.initials: HM
authors.lastname: Yang
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyun-Jae
authors.initials: HJ
authors.lastname: Kang
authors.forename: Bon-Kwon
authors.initials: BK
authors.lastname: Koo
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D000077144:Clopidogrel; D015331:Cohort Studies; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D054855:Drug-Eluting Stents; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine