CD80 DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome

Pei-Yuan Song; Mu-Peng Li; Li-Ming Peng; Xiao-Ping Chen

doi:10.1016/j.rpth.2023.100093

CD80 DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome

Res Pract Thromb Haemost. 2023 Feb 24;7(2):100093. doi: 10.1016/j.rpth.2023.100093. eCollection 2023 Feb.

Authors

Pei-Yuan Song^{1

2

3}, Mu-Peng Li^{1

2

3}, Li-Ming Peng^{1

2

3

4}, Xiao-Ping Chen^{1

2

3}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
² Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
⁴ Department of Cardiology, Xiangya Hospital, Central South University, Changsha, China.

Abstract

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 CD80_cg06300880 methylation. Carriers of rs34394661 AA genotype, a CpG-single-nucleotide polymorphism at the CD80_cg06300880 locus, showed an increased odds for HTPR (overall odds ratio of patients with ACS = 7.31, 95% CI: 1.69-31.59, P = .008; non-ST elevation myocardial infarction-ACS: odds ratio = 12.69, 95% CI: 1.68-96.08, P = .01) and decreased CD80_cg06300880 methylation (P < .0001). Multivariate regression analysis showed that both CYP2C19 poor metabolizers and CD80_rs34394661 AA (P = .009) genotype were associated with higher odds for HTPR in the overall samples. In contrast, CD80_cg06300880 methylation (P = .002) caused lower odds for HTPR in patients with non-ST elevation myocardial infarction-ACS.

Conclusion: CD80_cg06300880 and CpG-single-nucleotide polymorphism rs34394661 could be independent predictors of HTPR with clopidogrel therapy.

Keywords: DNA methylation; acute coronary syndrome (ACS); clopidogrel; platelet; single-nucleotide polymorphism (SNP).