Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: A systematic review and meta-analysis

Background: A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1-Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1-Q192R variant on the risk of MACE in clopidogrel-treated patients is controversial. Objectives: To determine whether the PON1-Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. Methods: Systematic review and meta-analysis of studies of the association between the PON1-Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. Results: Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n=5302 patients), there was no significant difference between 192QQ and 192QR+192RR subjects, whatever the laboratory method used (global mean standardized difference=0.10 [-0.06; 0.25], P=0.22). Eleven studies assessed the risk of MACE, four using a case-control design (n=2739 patients) and seven a prospective design (n=5353 patients). Overall, MACE occurred in 19% of patients in case-control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR+192RR patients (OR=1.28 [0.97; 1.68], P=0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. Conclusions: This meta-analysis suggests that the PON1-Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel-treated patients.