title: Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity.
abstract: OBJECTIVE
  To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG).
  
  
  METHODS
  One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed.
  
  
  RESULTS
  The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1and H2showed significantly lower incidences of HTPR than H0in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR.
  
  
  CONCLUSIONS
  The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.
authors.affiliation: School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Nie
authors.affiliation: School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jun-Lei
authors.initials: JL
authors.lastname: Li
authors.affiliation: Department of Cardiology, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Public Health, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Epidemiology, Fuwai Hospital, Beijing 100037, China.
authors.forename: Xue-Li
authors.initials: XL
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.affiliation: School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Guang-Kai
authors.initials: GK
authors.lastname: Liang
authors.affiliation: Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota 55415, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Cardiology, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lu-Wen
authors.initials: LW
authors.lastname: Shi
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy; D000368:Aged; D000483:Alleles; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D002681:China; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics*; D013916:Thrombelastography / Q000379:methods; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: C548576:P2RY12 protein, human; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine; D001241:Aspirin
keywords: P2RY12; CYP2C19; Haplotype; Single nucleotide polymorphism (SNP); Clopidogrel; Thromboelastography