title: Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke.
abstract: OBJECTIVE
  There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke.
  
  
  METHODS
  A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4(*)1G (rs2242480), CYP2C19(*)2 (rs4244285) and P2RY12 (rs2046934) were genotyped.
  
  
  RESULTS
  The CR rate in this population was 36%. The CYP2C19(*)2 variant was a risk factor for CR ((*)2/(*)2+wt/(*)2 vs wt/wt, OR: 2.366, 95% CI: 1.180-4.741, P=0.014), whereas the CYP3A4(*)1G variant had a protective effect on CR ((*)1/(*)1 vs (*)1G/(*)1G+(*)1/(*)1G, OR: 2.360, 95% CI: 1.247-4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286-0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs
  0.407, 95% CI: 0.191-0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022).
  
  
  CONCLUSIONS
  The individuals with both the CYP2C19(*)2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4(*)1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, China.
authors.forename: Zi-Yi
authors.initials: ZY
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yi-Bei
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Li
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Wei-Bang
authors.initials: WB
authors.lastname: Yu
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xin-Meng
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, China.
authors.forename: Yuan-Qi
authors.initials: YQ
authors.lastname: Zhao
authors.affiliation: Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, China.
authors.forename: Ye-Feng
authors.initials: YF
authors.lastname: Cai
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D065840:Protective Factors; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000188:drug therapy / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000625852:NR1I2 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D000077297:Pregnane X Receptor; D058925:Receptors, Purinergic P2Y12; D011987:Receptors, Steroid; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine