title: Variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest in clopidogrel pretreated patients undergoing coronary stenting.
abstract: BACKGROUND
  An inadequate response to clopidogrel is mainly attributable to the variable formation of its active metabolite. The CYP2C19*2 loss-of-function polymorphism leads to reduced generation of the active metabolite and is, similarly to high on-treatment platelet reactivity (HPR), associated with recurrent atherothrombotic events following coronary stent implantation.
  
  
  OBJECTIVE
  To determine the relative contribution of CYP2C19*2 genotype to HPR.
  
  
  RESULTS
  CYP2C19*2 genotyping and platelet function testing using 5 and 20 μmol/l ADP-induced light transmittance aggregometry (LTA), the PlateletWorks assay and the VerifyNow P2Y12 assay, were performed in 1069 clopidogrel pretreated patients undergoing elective coronary stenting (POPular study, http://clinicalTrials.gov/ NCT00352014). The relative contributions of CYP2C19*2 genotype and clinical variables to the interindividual variability of on-treatment platelet reactivity and the occurrence of HPR were established using multivariate regression models. CYP2C19*2 carrier status was associated with a more frequent occurrence of HPR. CYP2C19*2 genotype alone could explain 5.0%, 6.2%, 4.4% and 3.7% of the variability in 5 and 20 μmol/l ADP-induced LTA, the PlateletWorks assay and the VerifyNow P2Y12 assay, respectively, which increased to 13.0%, 15.2%, 5.6% and 20.6% when clinical variables were considered as well. Besides the CYP2C19*2 genotype, multiple clinical variables could be identified as independent predictors of HPR, including age, gender, body mass index, diabetes mellitus, clopidogrel loading dose regimen, use of amlodipine and platelet count.
  
  
  CONCLUSIONS
  The CYP2C19*2 loss-of-function polymorphism is associated with a more frequent occurrence of HPR. However, the part of the interindividual variability in on-treatment platelet reactivity explained by CYP2C19*2 genotype is modest.
authors.affiliation: Department of Cardiology, St Antonius Hospital, CM Nieuwegein, The Netherlands. jurtenberg@gmail.com
authors.forename: Heleen J
authors.initials: HJ
authors.lastname: Bouman
authors.forename: Ankie M
authors.initials: AM
authors.lastname: Harmsze
authors.forename: Jochem W
authors.initials: JW
authors.lastname: van Werkum
authors.forename: Nicoline J
authors.initials: NJ
authors.lastname: Breet
authors.forename: Th O
authors.initials: TO
authors.lastname: Bergmeijer
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hackeng
authors.forename: Vera H M
authors.initials: VH
authors.lastname: Deneer
authors.forename: Jurriën M
authors.initials: JM
authors.lastname: Ten Berg
mesh_terms: D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000379:methods; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics* / Q000628:therapy; D023903:Coronary Restenosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D065731:Cytochrome P-450 CYP2C19; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D057234:Preoperative Period; D011379:Prognosis; D011446:Prospective Studies; D015607:Stents; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D004247:DNA; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine