title: The effects of CES1A2 A(-816)C and CYP2C19 loss-of-function polymorphisms on clopidogrel response variability among Chinese patients with coronary heart disease.
abstract: OBJECTIVE
  Carboxylesterase 1 hydrolyzes the majority of clopidogrel to the inactive metabolite. The aim of this study was to assess the effects of the CES1A2 A(-816)C polymorphism and other genetic and clinical factors on clopidogrel response variability. An additional aim was to investigate the relationship between genetic variations and development of stent thrombosis (ST).
  
  
  METHODS
  We recruited 162 coronary heart disease patients treated with aspirin and clopidogrel, and we genotyped them for the CES1A2 A(-816)C, CYP2C19 *2/*3, PON1 Q192R, and ABCB1 C3435T polymorphisms. Platelet reactivity was analyzed using the VASP-PRI assay. We also carried out a case-control study in which 22 patients undergoing stent implantation who had ST were matched with 86 ST-free controls.
  
  
  RESULTS
  The VASP-PRI values were significantly higher in the carriers of the CES1A2 -816C allele (P=0.014) and CYP2C19 loss of function (LOF) alleles (P=0.004). Furthermore, the patients with CYP2C19 LOF alleles showed an increased risk of ST (ORadj=4.28, P=0.033). However, there was no significant association between the CES1A2 -816C allele and the development of ST. The CYP2C19 and CES1A2 genotypes alone could explain 6.1 and 3.7% of the interindividual variability in the VASP-PRI results, respectively. The value increased to 12.5% when clinical factors (e.g. BMI and triglycerides) were also considered. The PON1 Q192R and ABCB1 C3435T genetic variations produced no significant impact.
  
  
  CONCLUSIONS
  The CES1A2 -816C and the CYP2C19 LOF alleles were associated with attenuated platelet reactivity to clopidogrel. CYP2C19 LOF was also predictive of ST; however, the association between the CES1A2 -816C allele and development of ST requires further study.
authors.affiliation: aClinical Pharmacology Research Laboratory bDepartment of Cardiology, The First Affiliated Hospital of Soochow University cDepartment of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xie
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Ding
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Haipeng
authors.initials: H
authors.lastname: Wang
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Hang
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Liyan
authors.initials: L
authors.lastname: Miao
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000368:Aged; D043303:Aryldialkylphosphatase / Q000235:genetics; D001241:Aspirin / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D000077144:Clopidogrel; D003327:Coronary Disease / Q000235:genetics / Q000628:therapy*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D015607:Stents; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C121305:CES1P1 protein, human; D002265:Carboxylic Ester Hydrolases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D013988:Ticlopidine; D001241:Aspirin