Systematic review of the influence of DNA methylation level on the efficacy of P2Y12 receptor antagonists

The prescription of antiplatelet agents is an important part of the therapy for acute coronary syndrome and other cardiovascular diseases. The risk of recurrent ischemic events depends on the efficacy of these drugs.

The aim. To summarize and analyze current scientific data on the influence of DNA methylation level on the efficacy of therapy with P2Y12 receptor antagonists.

Materials and methods. A search for scientific articles was conducted in the PubMed database. The systematic review included studies reflecting the relationship between DNA methylation and the efficacy of clopidogrel. No studies were found concerning the influence of DNA methylation on the efficacy of next-generation P2Y12 receptor antagonists.

Results. The review included 17 studies with a total of 3 441 participants. The influence of methylation of 20 genes was analyzed: ABCB1, ABCC3, ALOX12, ALOX15, BTG2, CD80, COX1, COX2, CREB5, CYP2C19, GCK, GNAQ, P2Y12, PEAR1, PER3, PON1, PRG2, TRAF3, TBXAS1, VTRNA2-1. In 9 studies, a bond was found between methylation levels and the risk of developing clopidogrel resistance. In 5 studies, a bond was found between DNA methylation and the risk of developing adverse reactions such as bleeding or recurrent ischemic events. It was found that patients with hypomethylation of the CYP2C19 gene promoter have a higher risk of developing clopidogrel resistance (methylation level in the clopidogrel resistance group is 8.8 ± 22.7 %, in the control group — 76.7 ± 32.9 %, p = 0.03). Hypermethylation of the P2Y12 promoter also increases the risk of developing resistance to the drug (0.48 ± 0.14 % vs. 0.86 ± 0.13 %, p < 0.001).

Conclusion. The products of DNA methylation of genes are involved in clopidogrel metabolism, platelet aggregation, and other processes affects clopidogrel efficacy. DNA methylation level is a promising biomarker. Additional confirmatory studies are needed, as well as studies on the relationship between the methylation level and the efficacy of next-generation P2Y12 receptor antagonists.

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