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

Liu, X; Xu, H; Xu, H; Geng, Q; Mak, W-H; Ling, F; Su, Z; Yang, F; Zhang, T; Chen, J; Yang, H; Wang, J; Zhang, X; Xu, X; Jia, H; Zhang, Z; Liu, X; Zhong, S

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

Liu, X Xu, H

Xu, H

Geng, Q Mak, W-H Ling, F Su, Z Yang, F Zhang, T Chen, J Yang, H Wang, J Zhang, X Xu, X Jia, H Zhang, Z Liu, X Zhong, S

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Pharmacogenomics J, 2021, 21, (6), pp. 664-672
Issue Date:: 2021-12

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Field	Value	Language
dc.contributor.author	Liu, X
dc.contributor.author	Xu, H https://orcid.org/0000-0003-1129-5337
dc.contributor.author	Xu, H https://orcid.org/0000-0003-1129-5337
dc.contributor.author	Geng, Q
dc.contributor.author	Mak, W-H
dc.contributor.author	Ling, F
dc.contributor.author	Su, Z
dc.contributor.author	Yang, F
dc.contributor.author	Zhang, T
dc.contributor.author	Chen, J
dc.contributor.author	Yang, H
dc.contributor.author	Wang, J
dc.contributor.author	Zhang, X
dc.contributor.author	Xu, X
dc.contributor.author	Jia, H
dc.contributor.author	Zhang, Z
dc.contributor.author	Liu, X
dc.contributor.author	Zhong, S
dc.date.accessioned	2024-03-12T03:52:43Z
dc.date.available	2021-06-10
dc.date.available	2024-03-12T03:52:43Z
dc.date.issued	2021-12
dc.identifier.citation	Pharmacogenomics J, 2021, 21, (6), pp. 664-672
dc.identifier.issn	1470-269X
dc.identifier.issn	1473-1150
dc.identifier.uri	http://hdl.handle.net/10453/176547
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation.ispartof	Pharmacogenomics J
dc.relation.isbasedon	10.1038/s41397-021-00245-5
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Pharmacology & Pharmacy
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.subject.mesh	Acute Coronary Syndrome
dc.subject.mesh	Aged
dc.subject.mesh	Aspirin
dc.subject.mesh	Cardiovascular Diseases
dc.subject.mesh	Clopidogrel
dc.subject.mesh	Dual Anti-Platelet Therapy
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Machine Learning
dc.subject.mesh	Male
dc.subject.mesh	Middle Aged
dc.subject.mesh	Pharmacogenetics
dc.subject.mesh	Pharmacogenomic Testing
dc.subject.mesh	Pharmacogenomic Variants
dc.subject.mesh	Platelet Aggregation Inhibitors
dc.subject.mesh	Polymorphism, Single Nucleotide
dc.subject.mesh	Predictive Value of Tests
dc.subject.mesh	Risk Assessment
dc.subject.mesh	Risk Factors
dc.subject.mesh	Time Factors
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Exome Sequencing
dc.subject.mesh	Humans
dc.subject.mesh	Cardiovascular Diseases
dc.subject.mesh	Aspirin
dc.subject.mesh	Platelet Aggregation Inhibitors
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Risk Assessment
dc.subject.mesh	Risk Factors
dc.subject.mesh	Predictive Value of Tests
dc.subject.mesh	Pharmacogenetics
dc.subject.mesh	Polymorphism, Single Nucleotide
dc.subject.mesh	Time Factors
dc.subject.mesh	Aged
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Acute Coronary Syndrome
dc.subject.mesh	Machine Learning
dc.subject.mesh	Pharmacogenomic Variants
dc.subject.mesh	Pharmacogenomic Testing
dc.subject.mesh	Clopidogrel
dc.subject.mesh	Dual Anti-Platelet Therapy
dc.subject.mesh	Exome Sequencing
dc.subject.mesh	Acute Coronary Syndrome
dc.subject.mesh	Aged
dc.subject.mesh	Aspirin
dc.subject.mesh	Cardiovascular Diseases
dc.subject.mesh	Clopidogrel
dc.subject.mesh	Dual Anti-Platelet Therapy
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Machine Learning
dc.subject.mesh	Male
dc.subject.mesh	Middle Aged
dc.subject.mesh	Pharmacogenetics
dc.subject.mesh	Pharmacogenomic Testing
dc.subject.mesh	Pharmacogenomic Variants
dc.subject.mesh	Platelet Aggregation Inhibitors
dc.subject.mesh	Polymorphism, Single Nucleotide
dc.subject.mesh	Predictive Value of Tests
dc.subject.mesh	Risk Assessment
dc.subject.mesh	Risk Factors
dc.subject.mesh	Time Factors
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Exome Sequencing
dc.title	New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	United States
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Computer Science
utslib.copyright.status	open_access	*
dc.date.updated	2024-03-12T03:52:42Z
pubs.issue	6
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	6

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.

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http://hdl.handle.net/10453/176547