title: PON1 Q192R genotype influences clopidogrel responsiveness by relative platelet inhibition instead of on-treatment platelet reactivity.
abstract: BACKGROUND
  paraoxonase-1 (PON1) was recently identified as the crucial enzyme for clopidogrel bioactivation, with PON1 Q192R (rs662) polymorphism determining the clopidogel antiplatelet efficacy. However, subsequent studies showed controversies over the findings. This study aimed to evaluate the impact of PON1 Q192R in parallel to that of CYP2C19*2 (rs4244285) on clopidogrel responsiveness in a cohort of Chinese patients with unstable angina pectoris.
  
  
  METHODS
  One hundred and eighty Chinese-Han patients diagnosed with unstable angina pectoris and treated with clopidogrel were consecutively recruited. Clopidogrel responsiveness, measured by relative platelet inhibition {RI=[(pretreatment aggregation-posttreatment aggregation at 5days)/(pretreatment aggregation)] x100%}, was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. RI values were stratified into four quartiles, with patients in quartile 1 defined as individuals of clopidogrel non-responsiveness. The contributions of PON1 Q192R and CYP2C19*2 to on-treatment platelet reactivity (OTPR) at 5days maintenance dose of clopidogrel were also evaluated.
  
  
  RESULTS
  For PON1 Q192R genotypes, RI values were significantly lower in patients with QR and RR alleles than in patients with QQ alleles (p=0.01). OTPR values at 5days maintenance dose of clopidogrel were similar across all the PON1 Q192R genotypes (p=0.41). PON1 192 QR and RR conferred increased risks for clopidogrel non-responsiveness [OR 3.64; 95% CI (1.21-10.92), p=0.02]. For CYP2C19*2 genotypes, compared to CYP2C19*1/*1 wild type carriers, CYP2C19*2 carriers showed a significantly higher OTPR (p=0.009), and a trend for lower RI values (p=0.06). An increased risk for clopidogrel non-responsiveness was found in patients with CYP2C19*2 genotype [OR 2.02; 95% CI (1.03-3.96), p=0.04].
  
  
  CONCLUSIONS
  Both PON1 Q192R and CYP2C19*2 genotypes influence clopidogrel responsiveness, with the impact of PON1 Q192R mainly on relative platelet inhibition instead of OTPR of clopidogrel.
authors.affiliation: Institute of Geriatric Cardiology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Li
authors.forename: Lanning
authors.initials: L
authors.lastname: Zhang
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Qu
authors.forename: Jiayue
authors.initials: J
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Wang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Caiyi
authors.initials: C
authors.lastname: Lu
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
mesh_terms: D000789:Angina, Unstable / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077144:Clopidogrel; D015331:Cohort Studies; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D013988:Ticlopidine
keywords: CYP2C19; PON1; clopidogrel; platelet; responsiveness