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 ( CYP 450). 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 ) II b/ III a antagonist increased IPA ( P  <   0.05). ADP ‐induced IPA effect was lower with the presence of CYP 2C19 *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). CYP 2C19 *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 CYP 2C19 *2 and PON 1 Q192R LOF alleles were the major drivers of HPR .