New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

Xiaomin Liu,Zhiwei Zhang,Shilong Zhong,Xiuqing Zhang,Huanming Yang,Qingshan Geng,Huijue Jia,Tao Zhang,Jian Wang,Xun Xu,Xiao Liu,Zheng Su,Hanshi Xu,Jiyan Chen,Fang Yang,Wai-Ho Mak,Huaiqian Xu,Fei Ling

doi:10.1038/s41397-021-00245-5

Abstract

Although a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE end point during the 18-month follow-up period by a two-stage large-scale sequencing data, including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort. We discovered eight new genotypes and their genes associated with MACE in patients with ACS, including MYOM2 (rs17064642), WDR24 (rs11640115), NECAB1 (rs74569896), EFR3A (rs4736529), AGAP3 (rs75750968), ZDHHC3 (rs3749187), ECHS1 (rs140410716), and KRTAP10-4 (rs201441480). Notably, the expressions of MYOM2 and ECHS1 are downregulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting 18-month MACE and achieved high predictive performance (AUC ranged between 0.92 and 0.94 for three machine-learning methods). Our findings shed light on the pathogenesis of cardiovascular outcomes and may help the clinician to make a decision on the therapeutic intervention for ACS patients.

Highlights

As a standard treatment procedure for patients suffering from acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) with stenting, dual-antiplatelet therapy (DAPT) with clopidogrel in addition to aspirin, significantly reduces the risk of adverse cardiac events in patients [1]
Biological implications of variants associated with 18-month major adverse cardiovascular events (MACE) To further explore the functional evidence of the eight genes that contribute to 18-month MACE, we mined several publicly available genome-wide expression data sets from the Gene Expression Omnibus (GEO) database (Table S8) [23,24,25,26], which recorded cardiac remodeling data after myocardial infarction (MI)
To further explore the functional evidence of the eight genes that contribute to 18-month MACE, we searched all literatures referring to the eight genes and cardiovascular diseases in PubMed database, as well as mined previously reported publicly available GEO databases

Summary

Introduction

As a standard treatment procedure for patients suffering from ACS and those undergoing PCI with stenting, dual-antiplatelet therapy (DAPT) with clopidogrel in addition to aspirin, significantly reduces the risk of adverse cardiac events in patients [1]. Studies have reported the associations of several gene polymorphisms (CYP2C19*2, CYP2C19*3, CYP2C9*2, PON1 Q192R, and ABCB1 C3435T) with cardiovascular outcomes in patients with ACS and those undergoing PCI [3,4,5,6,7,8]. There are metaanalysis studies failed to support the associations of CYP2C19 and cardiovascular events [9, 10]. These studies about the effects of single-nucleotide variants (SNPs) on clinical outcomes were inconsistent and inconclusive. Genome-wide studies, such as whole-exome sequencing, should be conducted to enhance the understanding of this research field

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