title: Influence of Genetic Polymorphisms on Clopidogrel Response and Clinical Outcomes in Patients with Acute Ischemic Stroke CYP2C19 Genotype on Clopidogrel Response.
abstract: OBJECTIVE
  This study sought to evaluate the influence of the genetic polymorphisms on platelet reactivity and clinical outcomes in acute ischemic stroke patients taking clopidogrel.
  
  
  BACKGROUND
  Little research has been published on relationships between genetic polymorphisms, platelet reactivity, and clinical outcomes in stroke patients treated with clopidogrel.
  
  
  METHODS
  Patients hospitalized in Changhai Hospital with acute ischemic stroke were randomly enrolled into treatment with a 75-mg daily maintenance dose of clopidogrel. Genotyping was detected by the MassARRAY iPLEX genotyping system (Sequenom Inc, San Diego, CA), and platelet reactivity was evaluated by the VerifyNow P2Y12 test (Accumetrics Inc., San Diego, CA). Sixteen single nucleotide polymorphisms (SNPs) within 9 genes were selected and high on-clopidogrel platelet reactivity (HPR) was defined as P2Y12 reaction units (PRU) value ≥230. The primary endpoint was ischemic events, including major adverse cardiac events (MACE), recurrence of stroke, transient ischemic attack (TIA), and the composite of vascular death, and the secondary endpoint was bleeding.
  
  
  RESULTS
  Of the 345 patients recruited, 275 (79.7%) patients were followed up for 1 year and 122 (35.4%) patients were categorized as HPR. Among the SNPs selected, only the CYP2C19*2 allele and the CYP2C19*3 allele were statistically significantly associated with PRU (P < 0.001 and P = 0.003, respectively). Similarly, the prevalence of HPR was associated with CYP2C19*2 and CYP2C19*3 (P < 0.001 and P = 0.001, respectively). During the 1 year of follow-up, a total of 64 (23.3%) cases of clinical events occurred, including 60 ischemic events and 4 bleeding events. There were no correlation between CYP2C19 variant alleles and clinical outcomes (P > 0.05), but a statistically significant relevance was found between the HPR and the ischemic events in 1 year of follow-up (P = 0.001).
  
  
  CONCLUSIONS
  CYP2C19*2 and CYP2C19*3 had a significant impact on clopidogrel response, but was not associated with ischemic events during 1 year of follow-up in patients with acute ischemic stroke. HPR was an independent risk factor for ischemic events, and the VerifyNow P2Y12 test may be available to guide individualized antiplatelet therapies in stroke patients in China.
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Fudan Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Shi-Xu
authors.initials: SX
authors.lastname: Li
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Jiang
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: De-Sheng
authors.initials: DS
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Neurology, Changhai Hospital, Second Military Medical University, Shanghai, China.|Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yang-Tai
authors.initials: YT
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.|Fudan Center for Genetic Epidemiology, School of Life Sciences, Fudan University, Shanghai, China.|Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.|Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Xu
mesh_terms: D000368:Aged; D054316:Biomarkers, Pharmacological; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011897:Random Allocation; D020521:Stroke / Q000188:drug therapy* / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: CYP2C19; Clopidogrel; Ischemic stroke; The VerifyNow P2Y12 test