The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non‐ST acute coronary syndrome

Clopidogrel is a thienopyridine derivative that inhibits ADPinduced platelet aggregation. It is an inactive pro-drug that requires several biotransformation steps before it acquires its antiplatelet effect [1,2]. After intestinal absorption, clopidogrel requires oxidation by hepatic cytochrome P450 (CYP) to generate an active metabolite. This active metabolite inhibits platelet activation through irreversible binding to the platelet ADP receptor, P2Y12. Numerous studies have reported inter-individual variability in platelet response to clopidogrel, which is of clinical relevance with regard to patient treatment [3]. However, the mechanisms underlying this variability remain unclear. Putative explanations for variable clopidogrel response include genetic variations that influence the liver metabolism of clopidogrel. Several functional polymorphisms in genes encoding CYP have already been evaluated. Previous studies reported that the CYP3A4*1B and CYP3A5*3 polymorphisms could not explain the variability in the platelet inhibitory effects of clopidogrel [4,5]. In contrast, recent data have shown that the CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet response to clopidogrel in young healthy male volunteers [6] and in patients with coronary artery disease [7,8]. Moreover, this polymorphism has recently been associated with a poor clinical prognosis [9–11] and with an increased risk of thrombosis after coronary stent placement [12]. Recently, novel allelic variants of the CYP2C19 have been described including the CYP2C19*17 which is associated with ultrarapid enzyme activity and increased medication metabolism including omeprazole [13]. The aim of the present study was to evaluate the impact of these novel allelic variants of the CYP2C19 on platelet response to clopidogrel in patients suffering from non-ST elevation acute coronary syndrome (NSTE ACS). We therefore retrospectively evaluated 598 patients with NSTE ACS after the administration of a 600-mg clopidogrel loading dose, and the impact of CYP2C19*4 CYP2C19*5, CYP2C19*6 and CYP2C19*17 on platelet response to clopidogrel, as assessed using the maximal intensity of 10 lMADPinduced platelet aggregation (ADP-Ag) and by the platelet reactivity index vasodilator stimulated phosphoprotein assay (PRI VASP). All subjects analyzed in this retrospective study participated in a larger study conducted by the same organization to examine the effects of genetic polymorphisms involved in clopidogrel metabolism in NSTE ACS patients [7]. The baseline characteristics of the patients were: age 64.7 ± 12 years, 453 (76%) males, 169 (28%) had diabetes, 332 (56%) suffered from hypertension, 321 (54%) were dyslipidemic, 263 (44%) were current smokers, 336 (45%) were receiving statins, 271 (45%) were treated with betablockers and the body mass index (BMI) was 26.9 ± 4.3 kg.m. All patients were genotyped for CYP2C19*4, CYP2C19*5, CYP2C19*6 and CYP2C19*17. No significant deviations from Hardy–Weinberg equilibrium were observed for any of the genetic variants. Table 1 summarizes the observed frequencies of the CYP variants evaluated in the studied population. CYP2C19*4, CYP2C19*5 and CYP2C19*6 were very rare variants, whereas CYP2C19*17 was relatively common. The baseline characteristics of the patients did not differ between the different groups of genotypes. None of the polymorphisms (CYP2C19*4, CYP2C19*5 or CYP2C19*6) influenced platelet response to clopidogrel (C. Frere, T. Cuisset, B. Gaborit, M.-C. Alessi, J.-S. Hulot, unpublished data). In contrast, the CYP2C19*17 genotype was significantly associated with PRI VASP values, both in recessive (P = 0.02) and codominant (P = 0.0073) models (Table 2). After adjustment for factors that influence platelet reactivity (i.e. age, gender, BMI, diabetes and smoking status), this association remained Correspondence: Corinne Frere, Inserm, U626, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France. Tel. : +33 491324504; fax: +33 491254336. E-mail: corinne.frere@mail.ap-hm.fr