MicroRNAs as Novel Biomarkers for P2Y12 – Inhibitors Resistance Prediction

Abstract

The aim of this study is to assess 6 micro-RNAs: miR-126, miR-223, miR-150, miR-29, miR-34, miR-142 as potential biomarkers for P2Y12-inhibitors resistance prediction. Methods: Eighty patients with an acute coronary syndrome undergoing percutaneous coronary intervention treated in a multidisciplinary hospital in Moscow with DAPT (either with ticagrelor, n=45, or clopidogrel, n=35) were enrolled. The carriership of 6 clinically relevant polymorphisms for ticagrelor and 17 for clopidogrel was detected. Expression levels of six prospective miRNAs were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of cortisol and 6β-hydroxycortisol. Results:The polymorphisms of the P2Y12-inhibitors ADME genes that demonstrated statistically significant connection with miRNA expression levels are as follows: P2Y12R (A>G, rs3732759) and miR-29 (p=0.017), miR-34 (p=0.003); CYP2C19*17 (C-806T, rs1224856) and miR-142 (p=0.012); PON1 (Q192R, rs662) and miR-29 (p=0.004), ABCG2 (G>T, rs2231142) and miR-34 (p=0.007). MiRNAs expression levels showed connection with the results of the platelet reactivity assessment by utilizing VerifyNow assay ("Instrumentation laboratory", MA, US). MiR-126 (β coefficient=−0.076, SE=0.032, p=0.021), miR-223 (β coefficient=−0.089, SE=0.041, p=0.032), miR-29 (β coefficient=−0.042, SE=0.018, p=0.026), miR-142 (β coefficient=−0.072, SE=0.026, p=0.008) have the potential to be used as biomarkers and may substitute platelet reactivity testing. Conclusion:This study has revealed new biomarkers for P2Y12-inhibitors resistance testing: miR-29, miR-34, miR-126, miR-142, miR-223.

Influence of Genetic and Epigenetic Factors of P2Y12 Receptor on the Safety and Efficacy of Antiplatelet Drugs

“…Alteration in platelet aggregation due to reduced P2Y 12 expression caused by miRNA-126 inhibition was confirmed in patients with ACS [ 82 ]. In another study on that group of patients, the statistically significant connection between miRNA-29 and miRNA-34 expression levels and P2Y 12R gene polymorphism (A > G, rs3732759) was reported [ 83 ]. Syam et al [ 84 ] noticed a significant association of high miRNA-26a platelet expression but not DNA methylation of the P2Y 12 gene on platelet reactivity in patients with acute STEMI undergoing clopidogrel therapy.…”

Insights Into Platelet-Derived MicroRNAs in Cardiovascular and Oncologic Diseases: Potential Predictor and Therapeutic Target

“…A more recent study also reported that increased expression of miR-24-3p, miR-142-3p, and miR-411-3p was positively correlated with clopidogrel resistance (CR) in CAD patients ( 205 ). Similarly, miR-29, miR-34, miR-126, miR-142, and miR-223 are also reported to be novel biomarkers for P2Y12 inhibitor resistance prediction ( 206 ). Although the mechanisms of antiplatelet resistance are complex, the relationship between plasma miRNAs and platelet resistance may be explained by their regulation on platelet surface proteins.…”