title: Influence of genetic polymorphisms on the effect of high- and standard-dose clopidogrel after percutaneous coronary intervention: the GIFT (Genotype Information and Functional Testing) study.
abstract: OBJECTIVE
  This study sought to evaluate the influence of single nucleotide polymorphisms (SNPs) on the pharmacodynamic effect of high- or standard-dose clopidogrel after percutaneous coronary intervention (PCI).
  
  
  BACKGROUND
  There is a lack of prospective, multicenter data regarding the effect of different genetic variants on clopidogrel pharmacodynamics over time in patients undergoing PCI.
  
  
  METHODS
  The GRAVITAS (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety) trial screened patients with platelet function testing after PCI and randomly assigned those with high on-treatment reactivity (OTR) to either high- or standard-dose clopidogrel; a cohort of patients without high OTR were also followed. DNA samples obtained from 1,028 patients were genotyped for 41 SNPs in 17 genes related to platelet reactivity. After adjusting for clinical characteristics, the associations between the SNPs and OTR using linear regression were evaluated.
  
  
  RESULTS
  CYP2C19*2 was significantly associated with OTR at 12 to 24 h (R(2) = 0.07, p = 2.2 × 10(-15)), 30 days (R(2) = 0.10, p = 1.3 × 10(-7)), and 6 months after PCI (R(2) = 0.07, p = 1.9 × 10(-11)), whereas PON1, ABCB1 3435 C→T, and other candidate SNPs were not. Carriers of 1 and 2 reduced-function CYP2C19 alleles were significantly more likely to display persistently high OTR at 30 days and 6 months, irrespective of treatment assignment. The portion of the risk of persistently high OTR at 30 days attributable to reduced-function CYP2C19 allele carriage was 5.2% in the patients randomly assigned to high-dose clopidogrel.
  
  
  CONCLUSIONS
  CYP2C19, but not PON1 or ABCB1, is a significant determinant of the pharmacodynamic effects of clopidogrel, both early and late after PCI. In patients with high OTR identified by platelet function testing, the CYP2C19 genotype provides limited incremental information regarding the risk of persistently high reactivity with clopidogrel 150-mg maintenance dosing. (Genotype Information and Functional Testing Study [GIFT]; NCT00992420).
authors.affiliation: Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, California 92037, USA. price.matthew@scrippshealth.org
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Price
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Murray
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lillie
authors.forename: Erin N
authors.initials: EN
authors.lastname: Smith
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Tisch
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Paul S
authors.initials: PS
authors.lastname: Teirstein
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000235:genetics* / Q000628:therapy; D000483:Alleles; D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D010979:Platelet Function Tests; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
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