title: Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel.
abstract: Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: W-P
authors.initials: WP
authors.lastname: Zhong
authors.affiliation: Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: X-X
authors.initials: XX
authors.lastname: Li
authors.affiliation: Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: H-M
authors.initials: HM
authors.lastname: Lin
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Z-W
authors.initials: ZW
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: D-L
authors.initials: DL
authors.lastname: Ma
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: H-P
authors.initials: HP
authors.lastname: Li
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: L-P
authors.initials: LP
authors.lastname: Mai
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: G-D
authors.initials: GD
authors.lastname: He
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: X-P
authors.initials: XP
authors.lastname: Wang
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: H-P
authors.initials: HP
authors.lastname: Lei
authors.affiliation: Guangzhou Seq-Health Medical Technology Co., Ltd, Guangzhou, China.|Guangzhou Genedenovo Biotechnology Co., Ltd, Guangzhou, China.
authors.forename: H-K
authors.initials: HK
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: L
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: S-W
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.|Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: S-L
authors.initials: SL
authors.lastname: Zhong
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D001711:Biotransformation; D002681:China; D000077144:Clopidogrel; D003327:Coronary Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000071184:Pharmacogenomic Variants; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D020641:Polymorphism, Single Nucleotide; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D018570:Risk Assessment; D012307:Risk Factors; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000235:genetics* / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; C000607900:N6AMT1 protein, human; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific); D013988:Ticlopidine