The impact of P2Y12 promoter DNA methylation on the recurrence of ischemic events in Chinese patients with ischemic cerebrovascular disease

Abstract

The primary mechanism of clopidogrel resistance is still unclear. We aimed to investigate whether the methylation status of the P2Y12 promoter has effects on platelet function and clinical ischemic events. Patients with ischemic cerebrovascular disease were enrolled into our study. Venous blood samples were drawn for thrombelastograpy (TEG) and active metabolite assay. Patients were divided into a case- or control-group based on the occurrence of ischemic events during a one year follow-up. Two TEG parameters between the case and control groups were statistically significant [ADP inhibition rate (ADP%): P = 0.018; ADP-induced platelet-fibrin clot strength (MAADP): P = 0.030]. The concentrations of clopidogrel active metabolite had no significant difference (P = 0.281). Sixteen CpG dinucleotides on P2Y12 promoter were tested. Three CpG sites (CpG11 and CpG12 + 13) showed lower methylation status, which correlated with a strong association with increased risk of clinical events. Changes of MAADP and ADP% were also associated with methylation levels of CpG 11 and CpG 12 + 13. Hypomethylation of the P2Y12 promoter is associated with a higher platelet reactivity and increased risk of ischemic events in our patients. Methylation analysis of peripheral blood samples might be a novel molecular marker to help early identification of patients at high risk for clinical ischemic events.

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

“…The mechanical electrical transducer was used to test the status of clot in whole blood. The changes of amplitude were recorded by a computer during the thrombosis process . The largest change in the value of the amplitude of coagulation intensity was defined as the maximum clot strength (MA).…”

“…The changes of amplitude were recorded by a computer during the thrombosis process. 18 The largest change in the value of the amplitude of coagulation intensity was defined as the maximum clot strength (MA). The MA was classified into the thrombin-induced maximum coagulation strength (MA thrombin ), the 20 μmol/L ADP-induced maximum coagulation strength (MA ADP ) and the fibrin-induced maximum coagulation strength (MA Fibrin ) according to different types of activators added to the blood sample.…”

P2Y12 Polymorphisms and the Risk of Adverse Clinical Events in Patients Treated with Clopidogrel: A Meta-Analysis

“…Clopidogrel is a thienopyridine derivative inhibiting ADP-mediated platelet aggregation [35]. The active metabolite binds irreversibly and specifically to the P2Y12 platelet receptor.…”

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology

“…It is hypothesized that epigenetic modifications in the promotor or coding region, in response to certain physiologic or pathophysiologic states, can either activate or silence certain CYP450 enzymes. For example, methylation of CpG motifs (CpG11, CpG12, CpG13) in the promoter region for CYP2C19 was associated with HTPR and increased risk of ischemic events on clopidogrel [7,85,86]. If an allele is preferentially silenced via epigenetic modifications in the coding region, the complementary allele will be predominantly expressed.…”