Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel.
Clin Pharmacol Ther
; 101(6): 791-802, 2017 Jun.
Article
in En
| MEDLINE
| ID: mdl-27981573
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ticlopidine
/
Platelet Aggregation Inhibitors
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Site-Specific DNA-Methyltransferase (Adenine-Specific)
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Coronary Disease
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Polymorphism, Single Nucleotide
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Genetic Loci
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Purinergic P2Y Receptor Antagonists
/
ATP Binding Cassette Transporter 1
/
Pharmacogenomic Variants
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Country/Region as subject:
Asia
Language:
En
Journal:
Clin Pharmacol Ther
Year:
2017
Document type:
Article
Affiliation country:
China