Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

W-P Zhong; H Wu; J-Y Chen; X-X Li; H-M Lin; B Zhang; Z-W Zhang; D-L Ma; S Sun; H-P Li; L-P Mai; G-D He; X-P Wang; H-P Lei; H-K Zhou; L Tang; S-W Liu; S-L Zhong

doi:10.1002/cpt.589

Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

Clin Pharmacol Ther. 2017 Jun;101(6):791-802. doi: 10.1002/cpt.589. Epub 2017 Feb 9.

Authors

W-P Zhong^{1

2}, H Wu³, J-Y Chen^{1

2}, X-X Li², H-M Lin³, B Zhang^{1

2}, Z-W Zhang², D-L Ma^{1

2}, S Sun^{1

2}, H-P Li^{1

2}, L-P Mai², G-D He², X-P Wang², H-P Lei^{1

2}, H-K Zhou^{4

5}, L Tang⁶, S-W Liu⁶, S-L Zhong^{1

2}

Affiliations

¹ Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.
² Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
³ Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁴ Guangzhou Seq-Health Medical Technology Co., Ltd, Guangzhou, China.
⁵ Guangzhou Genedenovo Biotechnology Co., Ltd, Guangzhou, China.
⁶ Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.

PMID: 27981573
PMCID: PMC5485718
DOI: 10.1002/cpt.589

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.

MeSH terms

ATP Binding Cassette Transporter 1 / genetics*
ATP Binding Cassette Transporter 1 / metabolism
Aged
Biotransformation
China
Clopidogrel
Coronary Disease / diagnosis
Coronary Disease / drug therapy*
Coronary Disease / genetics
Female
Genetic Loci*
Genome-Wide Association Study
Humans
Male
Microsomes, Liver / metabolism
Middle Aged
Models, Biological
Nonlinear Dynamics
Pharmacogenomic Variants*
Platelet Aggregation Inhibitors / administration & dosage
Platelet Aggregation Inhibitors / adverse effects
Platelet Aggregation Inhibitors / pharmacokinetics*
Platelet Function Tests
Polymorphism, Single Nucleotide*
Purinergic P2Y Receptor Antagonists / administration & dosage
Purinergic P2Y Receptor Antagonists / adverse effects
Purinergic P2Y Receptor Antagonists / pharmacokinetics*
Receptors, Purinergic P2Y12 / blood
Receptors, Purinergic P2Y12 / drug effects
Risk Assessment
Risk Factors
Site-Specific DNA-Methyltransferase (Adenine-Specific) / genetics*
Site-Specific DNA-Methyltransferase (Adenine-Specific) / metabolism
Ticlopidine / administration & dosage
Ticlopidine / adverse effects
Ticlopidine / analogs & derivatives*
Ticlopidine / pharmacokinetics
Treatment Outcome

Substances

ABCA1 protein, human
ATP Binding Cassette Transporter 1
P2RY12 protein, human
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Receptors, Purinergic P2Y12
Clopidogrel
N6AMT1 protein, human
Site-Specific DNA-Methyltransferase (Adenine-Specific)
Ticlopidine