title: Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events.
abstract: BACKGROUND
  The prodrug clopidogrel requires activation by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding enzymes for clopidogrel activation are polymorphic, leading to reduced or increased function, depending on the respective genotype. Reduced-function alleles have been associated with an increase in cardiovascular events.
  
  
  METHODS
  We tested the association of the presence of the ABCB1 (C/T) T-allele, CYP2C19*2 (G/A) A-allele, or CYP2C19*17 (C/T) T-allele with the primary end point of the need of clinically-driven target lesion revascularization (TLR) and the secondary end points of major adverse cardiovascular events (MACE; including death, myocardial infarction [MI], and TLR) at 1 year in a high-risk population of 928 patients with acute MI.
  
  
  RESULTS
  Carriers of the CYP2C19*17 T-allele, with increased clopidogrel activation, had a 37% relative reduction in the TLR incidence, the primary end point (14.0% vs 22.3%, P = .002), and a 22% relative reduction of the secondary end point MACE (22.0% vs 28.1%, P = .04) compared with noncarriers, respectively. The association of the T-allele with TLR remained significant in the multivariate analysis (P = .001). The ABCB1 (C/T) and the CYP2C19*2 (G/A) polymorphisms were not associated with the incidence of TLR or MACE.
  
  
  CONCLUSIONS
  Based on the genetic analysis in a high-risk population of acute MI patients with interventional treatment and continuous clopidogrel therapy, our study found a protective effect for carriers of an increased-function CYP2C19*17 T-allele with significantly lower rates of TLR and MACE. T-allele carriers with acute MI and increased clopidogrel activation had significantly reduced clinical event rates.
authors.affiliation: Deutsches Herzzentrum München, Rechts der Isar, Technische Universität, Germany. klaustiroch@hotmail.com
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Tiroch
authors.forename: Dirk
authors.initials: D
authors.lastname: Sibbing
authors.forename: Werner
authors.initials: W
authors.lastname: Koch
authors.forename: Tobias
authors.initials: T
authors.lastname: Roosen-Runge
authors.forename: Julinda
authors.initials: J
authors.lastname: Mehilli
authors.forename: Albert
authors.initials: A
authors.lastname: Schömig
authors.forename: Adnan
authors.initials: A
authors.lastname: Kastrati
mesh_terms: D000368:Aged; D000483:Alleles; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000502:physiology*; D001711:Biotransformation; D002318:Cardiovascular Diseases / Q000235:genetics / Q000628:therapy; D000077144:Clopidogrel; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000517:prevention & control; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000235:genetics* / Q000628:therapy; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic / Q000502:physiology*; D012008:Recurrence; D012086:Reoperation; D015607:Stents; D020521:Stroke / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine