title: Gene variants in responsiveness to clopidogrel have no impact on clinical outcomes in Chinese patients undergoing percutaneous coronary intervention - A multicenter study.
abstract: BACKGROUND
  Gene variants contribute to variability in individual responsiveness to clopidogrel and influence cardiovascular outcomes in Caucasian patients with acute coronary syndrome (ACS). However, limited data is available in Asian populations.
  
  
  METHODS
  We resequenced 14 genes in metabolizing and activity pathway of clopidogrel in 138 patients with ACS and prospectively assessed the modulating effects of 13 variants possibly related to clopidogrel efficacy on one-year cardiovascular event occurrence in 5820 ACS patients after percutaneous coronary intervention (PCI). In addition, platelet aggregation rate was measured in 1084 participants and plasma levels of active metabolite were determined in 15 patients to test whether increasing clopidogrel maintenance doses increases active metabolite exposure.
  
  
  RESULTS
  No significant associations were found between any of the tested variants and risk of cardiovascular events (P>0.05), although CYP2C19*2 carriers had slightly higher on-treatment platelet aggregation rate and lower active metabolite exposure compared with that of non-carriers (Median [IQR] 51.49 [35.43-66.75] vs. 49.05 [32.36-63.38], P=0.012) (means±SD AUC, 22.84±5.00 vs. 35.05±12.34, P=0.008). Switching from 75mg daily clopidogrel to 150mg daily fully overcomes low exposure to clopidogrel active metabolite in CYP2C19*2 carriers (means±SD AUC, 32.35±8.65 vs. 35.05±12.34, P=0.314).
  
  
  CONCLUSIONS
  Different from Caucasian populations, genetic variants have no significant influence on clinical outcomes and have much milder effects on inhibition of platelet and active clopidogrel metabolite levels in Chinese patients with ACS after PCI, an effect which could be overcome with a dose escalation to 150mg daily.
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Chenze
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
authors.forename: Ling
authors.initials: L
authors.lastname: You
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Internal Medicine, Yuhuangding Hospital, Yantai City, Affiliated Hospital of Jining Medical College, Jining City, Shandong Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cardiology Division, Affiliated Hospital of Jining Medical College, Jining City, Shandong Province, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Hesong
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Guo
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China. Electronic address: lijianjun938@126.com.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Internal Medicine and Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; Department of Genetic diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China. Electronic address: dwwang@tjh.tjmu.edu.cn.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000235:genetics*; D000368:Aged; D044466:Asian People / Q000235:genetics*; D000077144:Clopidogrel; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention / Q000379:methods*; D000071184:Pharmacogenomic Variants / Q000187:drug effects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Clinical outcomes; Clopidogrel; Genetic