Background: Dual antiplatelet therapy with clopidogrel and aspirin is the primary treatment for patients who undergo percutaneous coronary intervention. However, the interindividual difference in clopidogrel response is remarkable, and high on-treatment platelet reactivity (HTPR) can increase the risk of thrombotic events after percutaneous coronary intervention.
Objective: We studied novel accessible factors that possibly affect clopidogrel response in DNA methylation.
Methods: Methylation 850K bead chips were used to detect DNA methylation levels. The platelet reactivity index (PRI) was determined in 330 subjects with acute coronary syndrome (ACS) after administration of clopidogrel 300 mg loading dose or at least 5 days of 75 mg daily maintenance dose.
Results: Overall, 32 discovery samples showed extreme clopidogrel response: 16 with HTPR (PRI > 75%) and 16 with non-HTPR (PRI < 26%). Overall, 61 differential methylation loci (DMLs) were observed between the 2 groups. Most were in the open sea and intergenic regions in the genome. In the validation stage, HTPR showed a lower level of cg06300880 methylation. Carriers of rs34394661 AA genotype, a CpG-single-nucleotide polymorphism at the cg06300880 locus, showed an increased odds for HTPR (overall odds ratio of patients with ACS = 7.31, 95% CI: 1.69-31.59, = .008; non-ST elevation myocardial infarction-ACS: odds ratio = 12.69, 95% CI: 1.68-96.08, = .01) and decreased cg06300880 methylation ( < .0001). Multivariate regression analysis showed that both poor metabolizers and rs34394661 AA ( = .009) genotype were associated with higher odds for HTPR in the overall samples. In contrast, cg06300880 methylation ( = .002) caused lower odds for HTPR in patients with non-ST elevation myocardial infarction-ACS.
Conclusion: cg06300880 and CpG-single-nucleotide polymorphism rs34394661 could be independent predictors of HTPR with clopidogrel therapy.
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| http://dx.doi.org/10.1016/j.rpth.2023.100093 | DOI Listing |
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