Recent advances in the pharmacogenetics of clopidogrel |
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Authors: | Thomas Cuisset Pierre-Emmanuel Morange Marie-Christine Alessi |
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Affiliation: | (1) Department of Cardiology, CHU Timone, Marseille, France;(2) Laboratory of Hematology, CHU Timone, Marseille, France;(3) Faculty of Medicine, UMR Inserm 626, Marseille, France;; |
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Abstract: | Clopidogrel has been used to prevent recurrent ischemic events after acute coronary syndrome and/or coronary stent implantation.
An impaired platelet response to this drug (residual high platelet reactivity) has been identified as a risk factor for recurrent
ischemic events. The platelet response to clopidogrel is highly heritable (73%) suggesting a substantial genetic component.
Two sequential cytochrome P450-dependent oxidative steps are required to convert clopidogrel to its active metabolite. The
first step leads to the formation of 2-oxo-clopidogrel, which is then metabolized to the active metabolite. Cytochrome P450s
are large highly polymorphic family of mono-oxygenases. Many alleles have been reported, and some of these are able to modify
the activity of proteins, reducing or increasing the concentration of active metabolites and the drug effect. Loss-of-function
variants in the hepatic cytochrome 2C19 (mainly *2 allele) system have been found to be the predominant genetic mediators
of clopidogrel response. Variant carriers have higher treatment platelet reactivity and higher risk of adverse cardiac events
including stent thrombosis, myocardial infarction, and death. Although value of CYP2C19 genotyping has been demonstrated in
ACS population treated with PCI, there is still a wide interindividual variability within each genotype to systematically
advocate this genetic testing in clinical practice. The CYP2C19*2 variant only explained 12% of the platelet response to clopidogrel.
In the near future, it is highly probable that additional gene variants or epigenetic phenomenon will emerge as significant
contributors to clopidogrel response that will allow recommending genetic testing for routine use. The purpose of this review
is to discuss the contribution of individual genetic differences responsible for variations of action and clopidogrel efficacy. |
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