The CYP2C19*17 variant is not independently associated with clopidogrel response

Abstract

SUMMARY Background Cytochrome P450 2C19 (CYP2C19) is the principle enzyme responsible for converting clopidogrel into its active metabolite and genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity/expression. Objective We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). Patients/Methods We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and ADP-stimulated platelet aggregation pre- and post-clopidogrel exposure. Results The CYP2C19*2 and CYP2C19*17 variants were in LD (|D’|=1.0; r2=0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (beta=−5.24, P=3.0×10−9 and beta=−5.36, P=3.3×10−14, respectively) and post-treatment ADP-stimulated platelet aggregation (beta=7.55, P=2.9×10−16 and beta=7.51, P=7.0×10−15, respectively). In contrast, CYP2C19*17 was associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (beta=1.57, P=0.04 and beta=−1.98, P=0.01, respectively) but not after (beta=0.40, P=0.59 and beta=−0.13, P=0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. Conclusions Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant.

Benefits of laboratory personalized antiplatelet therapy in patients undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials

“…More studies performed at later dates confirmed this correlation [38][39][40]. CYP2C19*17 gain-of--function gene is related to a reactivity increase of clopidogrel, but recent studies found that this correlation may be due to CYP2C19*2 linkage disequilibrium [41]. However, prasugrel is not significantly influenced by gene polymorphism, although some studies suggest an association [42,43].…”

Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records

“…On the other hand, CYP2C19*17 allele has been associated with enhanced clopidogrel response and increased risk of bleeding in some studies. [25][26][27][28] Variants in other genes, including ABCB1, CES1, and PON1, have been suggested to play a role in the interindividual variability of clopidogrel response, but these results have not been widely replicated. 27,29,30 A further weakness is that we were unable to include data in relation to medical or other treatments during the time period in the hospital with information on treatment coming entirely from redemption of prescriptions from community pharmacies.…”

Genetics of Clopidogrel Resistance: Recent Data

“…Снижение риска ишемических осложнений и повышение риска кровотечения подтверждают результаты двух независимых мета-анализов -Li Y, et al [27] и Zabalza M, et al [28]. Тем не менее, клиниче-ское значение CYP2C19*17, на сегодняшний день, остается спорным, и ряд исследований подтверждают отсутствие независимого влияния данного полимор-физма на метаболизм клопидогреля [29]. А усиление антиагрегантного действия клопидогреля при высо-кой частоте носительства CYP2C19*17 авторы связы-вают с часто сопутствующим этому, отсутствием или уменьшением частоты носительства CYP2C19 *2 [29].…”