Objectives Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genotypes in these genes have been associated with the variability of responsiveness to clopidogrel, however their contribution to clopidogrel antiplatelet efficacy in clinical practice is controversy. This study aimed to evaluate the contribution of the genotypes in CYP2C19, ABCB1 and PON1 to clopidogrel antiplatelet efficacy in a cohort of Chinese patients with acute coronary syndrome.
Methods A total of 1,329 Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People’s Liberation Army, from September 2008 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, the risk for high on-treatment platelet reactivity (HPR), as well as the risk for clinical ischaemic events. The cutoff of HPR was defined as 20 μmol/L adenosine diphosphate (ADP)-induced platelet aggregation >50%. The primary ischaemic endpoints were a composite of cardiovascular death, myocardial infarction, stent thrombosis, urgent revascularisation, and fatal or nonfatal stroke. The follow-up interval for each case was 12 months.
Results Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P < 0.001 and P = 0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (CYP2C19*2 or *3) was obviously higher than that in non-carriers (P < 0.001). The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR: 1.79, 95% CI: 1.33-2.4, P = 0.003). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype (adjusted HR: 1.56; 95% CI, 1.04-2.33, P = 0.03). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly. During follow-up, carriers of CYP2C19 loss-of-function alleles did not have an increased rate of primary or secondary ischaemic endpoints. No significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation or ischaemic events could be found.
Conclusions In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. However, no relationship was seen between CYP2C19 genotypes and ischaemic outcomes. Neither ABCB1 nor PON1 genotype could influence the antiplatelet efficacy of clopidogrel.