Clopidogrel-associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y(12) antagonist) is commonly used to prevent re-infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y(12) antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro-drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel-associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end-point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on-treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on-treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP-induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss-of-function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA-induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672-8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1-year post PCI operations (OR = 2.571; 95% CI: 1.143-5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.