title: CYP2C19 polymorphisms and coronary heart disease risk factors synergistically impact clopidogrel response variety after percutaneous coronary intervention.
abstract: BACKGROUND
  Platelet inhibition by clopidogrel is highly variable and the elevated platelet activity will increase the risk of major adverse cardiovascular events after percutaneous coronary intervention (PCI). CYP2C19 loss-of-function (LOF) alleles and risk factors of coronary heart disease (CAD) were reported to be associated with the low response of clopidogrel.
  
  
  OBJECTIVE
  This study was carried out to analyze the contributions of CYP2C19 polymorphisms and risk factors to the various clopidogrel responses in Chinese patients with stable CAD after PCI.
  
  
  METHODS
  The platelet reactivity index (PRI) was measured in 145 patients who underwent PCI using the vasodilator-stimulated phosphoprotein assay. Gene chip hybrid tests were used to analyze the genetic polymorphisms of CYP2C19.
  
  
  RESULTS
  With a cutoff value of 50% in PRI, 20.67% (31/145) of the patients were defined to be clopidogrel resistant. With respect to the normal *1, *2, and *3 LOF CYP2C19 alleles, patients were classified into three metabolism phenotypes: 39.31% were extensive, 47.59% were intermediate, and 13.10% were poor metabolizers (PMs). Of the enrolled patients, 53.82 and 9.66%, respectively, were carriers of *2 and *3 alleles. There was a significant difference in PRI between PM and either extensive or intermediate metabolizers (P<0.05). In all, 36.84% of the patients with the PM phenotype were clopidogrel resistant. Carriers of two CYP2C19 LOF alleles, BMI, and the presence of type 2 diabetes were three independent risk factors for clopidogrel resistance.
  
  
  CONCLUSIONS
  Genetic CYP2C19 polymorphisms and CAD risk factors - type 2 diabetes mellitus and BMI - synergistically affect the antiplatelet activity of clopidogrel and the occurrence of major adverse cardiovascular events after PCI.
authors.affiliation: Departments of aCardiology bRespiratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Song
authors.forename: Jin
authors.initials: J
authors.lastname: Yu
authors.forename: Rui
authors.initials: R
authors.lastname: Si
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: He
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Guo
authors.forename: Hai-Chang
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015992:Body Mass Index; D015815:Cell Adhesion Molecules / Q000097:blood; D002681:China; D000077144:Clopidogrel; D003327:Coronary Disease / Q000097:blood / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects / Q000401:mortality; D010597:Pharmacogenetics; D010641:Phenotype; D010750:Phosphoproteins / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine