35 Pierre Fontana1,2 and Jean-Luc Reny1,2,3 1 Geneva Platelet Group, University of Geneva, Geneva, Switzerland 2 Trois-Chêne, Hospital, Geneva, Switzerland 3 Geneva University Hospitals and, Faculty of Medicine (Geneva Platelet Group), Geneva, Switzerland At least one-third of patients treated with clopidogrel display high on-treatment platelet reactivity (HTPR) and are potentially not adequately protected from recurrent major adverse cardiovascular events (MACE) [1]. The prognostic value of HTPR is particularly important in acute coronary syndromes and becomes much less relevant as the clinical condition is more stable [2, 3]. Although some clinically meaningful cutoffs have been consensually suggested for some platelet function assays defining HTPR [4], there remain some uncertainties with regard to the universal value of such cutoffs. Moreover, uncertainties relate also to the platelet function assay to be used since they do not necessarily identify the same patients as having HTPR. A genetic approach to identify patients at risk is thus tempting since fast, cheap, and reliable genotyping is around the corner. Indeed, the important variability of the biological response to clopidogrel is hardly explained by demographic factors [5], while it is believed to be highly heritable (h 2 = 0.73) [6], suggesting an important genetic contribution. This has prompted a quest for genetic culprits, starting with a conventional candidate gene approach and evolving to next-generation sequencing strategies. The first attempt to unravel the genetic basis of clopidogrel response variability was based on the identification of associations between genetic variations within prespecified genes of interest and the biological response to clopidogrel (candidate gene approach). This approach implies thorough knowledge of genes implicated in clopidogrel metabolism including absorption, activation of the prodrug, and degradation [7]. Although clopidogrel is on the market for about 15 years, its exact metabolism is not fully understood and represents a field of active research. Clopidogrel absorption is mediated by the efflux transporter P-glycoprotein (P-gp) that is encoded by the ABCB1 (MDR1) gene [8]. The ABCB1 gene is highly polymorphic, and one variant (C3435T in exon 26 [rs1045642]) was evaluated in several studies. Although the initial publication clearly showed an association between this latter polymorphism and the pharmacokinetic profile of clopidogrel [8], its association with the recurrence of ischemic cardiovascular events was more mitigated with a recent meta-analysis showing no significant association with clinical events [9]. After the absorption of the prodrug, clopidogrel is exposed to carboxylesterases that hydrolyzed around 85% of the molecule into an inactive carboxyl metabolite. Recent data showed indeed the implication of carboxylesterase 1 as well as a genetic variant (G143E, rs71647871) associated with clopidogrel response [10, 11]. The remaining approximately 15% of the drug absorbed undergoes a two-step oxidation process by hepatic cytochromes P450 (CYPs) resulting in 2-oxo-clopidogrel followed by the opening of the thiophene group to the thiol metabolite. The cis-thiol metabolite inhibits covalently the platelet ADP receptor P2Y12 [12]. Various CYPs are implicated in this activation process including CYP3A4, CYP2C19, CYP2C9, and CYP2B6 [12]. CYP2C19 drew a particular attention due to its relative large contribution in the activation of clopidogrel [12], and carriers of loss-of-function genetic variants in the CYP2C19 gene have been consistently associated with lower active clopidogrel metabolite levels and diminished platelet inhibition. Table 35.1 summarized the allelic frequency in different populations of various loss- and gain-of-function CYP2C19 genetic variants [13]. The first description of the impact of a genetic variant of the CYP2C19 gene on the biological response to clopidogrel was by the publication of Hulot et al. [14] and Fontana et al. [15] who evaluated the association of the loss-of-function CYP2C19*2 allele (rs4244285) with platelet reactivity in clopidogrel-treated healthy subjects. When considering the distributions of the platelet response to clopidogrel according to the CYP2C19*1/*2 status, a large overlap is obvious (Figure 35.1). Thus, based on a 50% VASP assay cutoff [4], a significant proportion of CYP2C19*2 carriers have an “adequate” response to clopidogrel, while another important proportion of CYP2C19*2 noncarriers are clopidogrel poor responders [7, 16]. This reflects the fact that the CYP2C19*1/*2 genotype has only a minor influence (5–12%) on the pharmacodynamic response to clopidogrel [6, 16, 17, 18, 5]. In the same line, the association between CYP2C19*2 and the recurrence of ischemic events in clopidogrel-treated patients yielded mitigated results with recent meta-analyses showing a poor predictive value of this polymorphism, mostly related to a small study bias effect and restricted to stent thrombosis [19, 20, 21]. Thus, a strategy of routine antiplatelet drug tailoring according to CYP2C19*1/*2 would be limited to improving the rate of stent thrombosis with the risk of overlooking an important proportion of CYP2C19*2 noncarriers bearing HTPR (false-negatives of genetic testing) who are at increased risk for ischemic events. Table 35.1 Allelic frequency of common functional alleles of the CYP2C19 gene.
Genetics of Clopidogrel Poor Response
Introduction
Candidate gene approach
Allelic frequency
CYP2C19 variant
Impact of DNA change
Europeans
Asians
*2 (rs4244285)
Splicing defect
0.12–0.16
0.29
*3 (rs1057910)
Premature stop codon
<0.01
0.04–0.12
*17 (rs12248560)
Increased gene transcription
0.19–0.27
0.01
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