The role of clopidogrel resistance-related genetic and epigenetic factors in major adverse cardiovascular events among patients with acute coronary syndrome after percutaneous coronary intervention

Astuti Giantini; Ina S Timan; Rahajuningsih Dharma; Renan Sukmawan; Rianto Setiabudy; Idrus Alwi; Alida R Harahap; Erlin Listiyaningsih; Lia G Partakusuma; Arif R Tansir; Windy Sahar; Rakhmad Hidayat

doi:10.3389/fcvm.2022.1027892

The role of clopidogrel resistance-related genetic and epigenetic factors in major adverse cardiovascular events among patients with acute coronary syndrome after percutaneous coronary intervention

Front Cardiovasc Med. 2023 Feb 8:9:1027892. doi: 10.3389/fcvm.2022.1027892. eCollection 2022.

Authors

Affiliations

¹ Clinical Pathology Department, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Public Hospital, Central Jakarta, Indonesia.
² Universitas Indonesia Hospital, Universitas Indonesia, Depok, Indonesia.
³ Cardiology and Vascular Medicine Department, Faculty of Medicine, Universitas Indonesia, National Cardiovascular Center Harapan Kita, West Jakarta, Indonesia.
⁴ Pharmacology and Therapeutics Department, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Public Hospital, Central Jakarta, Indonesia.
⁵ Internal Medicine Department, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Public Hospital, Central Jakarta, Indonesia.
⁶ National Cardiovascular Center Harapan Kita, West Jakarta, Indonesia.
⁷ Faculty of Medicine, Universitas Indonesia, Central Jakarta, Indonesia.
⁸ Neurology Department, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo National Public Hospital, Central Jakarta, Indonesia.

Abstract

Despite patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and receiving clopidogrel therapy, some patients still experience major adverse cardiovascular events (MACEs). Clopidogrel resistance, which may be regulated by genetic and epigenetic factors, may play a role in MACEs. This study aimed to determine the association between genetic (CYP2C19 and P2Y12 polymorphisms) and epigenetic (DNA methylation of CYP2C19 and P2Y12 and miRNA-26a expression) factors and their effects on MACEs among post-PCI patients. Post-PCI patients who received a standard dosage of clopidogrel at Harapan Kita Hospital between September 2018 and June 2020 were included in this study. MACEs were observed in patients within 1 year after PCI. Platelet aggregation was assessed using light transmission aggregometry (LTA). DNA methylation of CYP2C19 and P2Y12 was assessed using the bisulfite conversion method. CYP2C19 and P2Y12 polymorphisms and miRNA-26a expression were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Among a total of 201 subjects, 49.8% were clopidogrel-resistant, and 14.9% experienced MACEs within 1 year after PCI (death was 7.5%). Hypomethylation of CYP2C19 (p = 0.037) and miRNA-26a upregulation (p = 0.020) were associated with clopidogrel resistance. CYP2C19^*2/^*3 polymorphisms (p = 0.047) were associated with MACEs in 1 year. This study demonstrated that hypomethylation of CYP2C19 and miRNA-26a upregulation increased the risk of clopidogrel resistance in post-PCI patients, but there was no correlation between clopidogrel resistance and MACEs. However, CYP2C19^*2/^*3 polymorphisms were the factors that predicted MACEs within 1 year.

Keywords: acute coronary syndrome; clopidogrel resistance; epigenetic factor; genetic factor; major adverse cardiovascular events.

Grants and funding

This research was supported by the grant of Riset Unggulan Harapan Kita (RUHK) from the National Cardiovascular Center Harapan Kita.