Contribution of exome sequencing to the identification of genes involved in the response to clopidogrel in cardiovascular patients.
Details
Serval ID
serval:BIB_310A8D0307B7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Contribution of exome sequencing to the identification of genes involved in the response to clopidogrel in cardiovascular patients.
Journal
Journal of thrombosis and haemostasis
ISSN
1538-7836 (Electronic)
ISSN-L
1538-7836
Publication state
Published
Issued date
06/2020
Peer-reviewed
Oui
Volume
18
Number
6
Pages
1425-1434
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
On-clopidogrel platelet reactivity (PR) is associated with the risk of thrombotic or bleeding event in selected populations of high-risk patients. PR is a highly heritable phenotype and a few variants of cytochrome genes, essentially CYP2C19, are associated with PR but only explain 5% to 12% of the variability.
The aim of this study is to delineate genetic determinants of on-clopidogrel PR using high-throughput sequencing.
We performed a whole exome sequencing of 96 low- and matched high-PR patients in a discovery cohort. Exomes from genes with variants significantly associated with PR were sequenced in 96 low- and matched high-PR patients from an independent replication cohort.
We identified 585 variants in 417 genes with an adjusted P value < .05. In the replication cohort, all top variants including CYP2C8, CYP2C18, and CYP2C19 from the discovery population were found again. An original network analysis identified several candidate genes of potential interest such as a regulator of PI3K, a key actor in the downstream signaling pathway of the P2Y <sub>12</sub> receptor.
This study emphasizes the role of CYP-related genes as major regulators of clopidogrel response, including the poorly investigated CYP2C8 and CYP2C18.
The aim of this study is to delineate genetic determinants of on-clopidogrel PR using high-throughput sequencing.
We performed a whole exome sequencing of 96 low- and matched high-PR patients in a discovery cohort. Exomes from genes with variants significantly associated with PR were sequenced in 96 low- and matched high-PR patients from an independent replication cohort.
We identified 585 variants in 417 genes with an adjusted P value < .05. In the replication cohort, all top variants including CYP2C8, CYP2C18, and CYP2C19 from the discovery population were found again. An original network analysis identified several candidate genes of potential interest such as a regulator of PI3K, a key actor in the downstream signaling pathway of the P2Y <sub>12</sub> receptor.
This study emphasizes the role of CYP-related genes as major regulators of clopidogrel response, including the poorly investigated CYP2C8 and CYP2C18.
Keywords
Clopidogrel/pharmacology, Clopidogrel/therapeutic use, Cytochrome P-450 CYP2C19/genetics, Exome, Genotype, Humans, Platelet Aggregation, Platelet Aggregation Inhibitors/adverse effects, Ticlopidine/adverse effects, Whole Exome Sequencing, clopidogrel, drug response, exome sequencing, network analysis, platelet reactivity
Pubmed
Web of science
Create date
27/02/2020 17:05
Last modification date
30/05/2021 6:35
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