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Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes

Increasing evidence has indicated that modulation of epigenetic mechanisms, especially methylation and long-non-coding RNA (lncRNA) regulation, plays a pivotal role in the process of atherosclerosis; however, few studies focused on revealing the epigenetic-related subgroups during atherosclerotic pr...

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Autores principales: Xue, Yuzhou, Guo, Yongzheng, Luo, Suxin, Zhou, Wei, Xiang, Jing, Zhu, Yuansong, Xiang, Zhenxian, Shen, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767999/
https://www.ncbi.nlm.nih.gov/pubmed/33381146
http://dx.doi.org/10.3389/fgene.2020.569572
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author Xue, Yuzhou
Guo, Yongzheng
Luo, Suxin
Zhou, Wei
Xiang, Jing
Zhu, Yuansong
Xiang, Zhenxian
Shen, Jian
author_facet Xue, Yuzhou
Guo, Yongzheng
Luo, Suxin
Zhou, Wei
Xiang, Jing
Zhu, Yuansong
Xiang, Zhenxian
Shen, Jian
author_sort Xue, Yuzhou
collection PubMed
description Increasing evidence has indicated that modulation of epigenetic mechanisms, especially methylation and long-non-coding RNA (lncRNA) regulation, plays a pivotal role in the process of atherosclerosis; however, few studies focused on revealing the epigenetic-related subgroups during atherosclerotic progression using unsupervised clustering analysis. Hence, we aimed to identify the epigenetics-related differentially expressed genes associated with atherosclerosis subtypes and characterize their clinical utility in atherosclerosis. Eighty samples with expression data (GSE40231) and 49 samples with methylation data (GSE46394) from a large artery plaque were downloaded from the GEO database, and aberrantly methylated–differentially expressed (AMDE) genes were identified based on the relationship between methylation and expression. Furthermore, we conducted weighted correlation network analysis (WGCNA) and co-expression analysis to identify the core AMDE genes strongly involved in atherosclerosis. K-means clustering was used to characterize two subtypes of atherosclerosis in GSE40231, and then 29 samples were recognized as validation dataset (GSE28829). In a blood sample cohort (GSE90074), chi-square test and logistic analysis were performed to explore the clinical implication of the K-means clusters. Furthermore, significance analysis of microarrays and prediction analysis of microarrays (PAM) were applied to identify the signature AMDE genes. Moreover, the classification performance of signature AMDE gene-based classifier from PAM was validated in another blood sample cohort (GSE34822). A total of 1,569 AMDE mRNAs and eight AMDE long non-coding RNAs (lncRNAs) were identified by differential analysis. Through the WGCNA and co-expression analysis, 32 AMDE mRNAs and seven AMDE lncRNAs were identified as the core genes involved in atherosclerosis development. Functional analysis revealed that AMDE genes were strongly related to inflammation and axon guidance. In the clinical analysis, the atherosclerotic subtypes were associated with the severity of coronary artery disease and risk of adverse events. Eight genes, including PARP15, SERGEF, PDGFD, MRPL45, UBR1, STAU1, WIZ, and LSM4, were selected as the signature AMDE genes that most significantly differentiated between atherosclerotic subtypes. Ultimately, the area under the curve of signature AMDE gene-based classifier for atherosclerotic subtypes was 0.858 and 0.812 in GSE90074 and GSE34822, respectively. This study identified the AMDE genes (lncRNAs and mRNAs) that could be implemented in clinical clustering to recognize high-risk atherosclerotic patients.
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spelling pubmed-77679992020-12-29 Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes Xue, Yuzhou Guo, Yongzheng Luo, Suxin Zhou, Wei Xiang, Jing Zhu, Yuansong Xiang, Zhenxian Shen, Jian Front Genet Genetics Increasing evidence has indicated that modulation of epigenetic mechanisms, especially methylation and long-non-coding RNA (lncRNA) regulation, plays a pivotal role in the process of atherosclerosis; however, few studies focused on revealing the epigenetic-related subgroups during atherosclerotic progression using unsupervised clustering analysis. Hence, we aimed to identify the epigenetics-related differentially expressed genes associated with atherosclerosis subtypes and characterize their clinical utility in atherosclerosis. Eighty samples with expression data (GSE40231) and 49 samples with methylation data (GSE46394) from a large artery plaque were downloaded from the GEO database, and aberrantly methylated–differentially expressed (AMDE) genes were identified based on the relationship between methylation and expression. Furthermore, we conducted weighted correlation network analysis (WGCNA) and co-expression analysis to identify the core AMDE genes strongly involved in atherosclerosis. K-means clustering was used to characterize two subtypes of atherosclerosis in GSE40231, and then 29 samples were recognized as validation dataset (GSE28829). In a blood sample cohort (GSE90074), chi-square test and logistic analysis were performed to explore the clinical implication of the K-means clusters. Furthermore, significance analysis of microarrays and prediction analysis of microarrays (PAM) were applied to identify the signature AMDE genes. Moreover, the classification performance of signature AMDE gene-based classifier from PAM was validated in another blood sample cohort (GSE34822). A total of 1,569 AMDE mRNAs and eight AMDE long non-coding RNAs (lncRNAs) were identified by differential analysis. Through the WGCNA and co-expression analysis, 32 AMDE mRNAs and seven AMDE lncRNAs were identified as the core genes involved in atherosclerosis development. Functional analysis revealed that AMDE genes were strongly related to inflammation and axon guidance. In the clinical analysis, the atherosclerotic subtypes were associated with the severity of coronary artery disease and risk of adverse events. Eight genes, including PARP15, SERGEF, PDGFD, MRPL45, UBR1, STAU1, WIZ, and LSM4, were selected as the signature AMDE genes that most significantly differentiated between atherosclerotic subtypes. Ultimately, the area under the curve of signature AMDE gene-based classifier for atherosclerotic subtypes was 0.858 and 0.812 in GSE90074 and GSE34822, respectively. This study identified the AMDE genes (lncRNAs and mRNAs) that could be implemented in clinical clustering to recognize high-risk atherosclerotic patients. Frontiers Media S.A. 2020-12-14 /pmc/articles/PMC7767999/ /pubmed/33381146 http://dx.doi.org/10.3389/fgene.2020.569572 Text en Copyright © 2020 Xue, Guo, Luo, Zhou, Xiang, Zhu, Xiang and Shen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Xue, Yuzhou
Guo, Yongzheng
Luo, Suxin
Zhou, Wei
Xiang, Jing
Zhu, Yuansong
Xiang, Zhenxian
Shen, Jian
Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes
title Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes
title_full Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes
title_fullStr Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes
title_full_unstemmed Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes
title_short Aberrantly Methylated-Differentially Expressed Genes Identify Novel Atherosclerosis Risk Subtypes
title_sort aberrantly methylated-differentially expressed genes identify novel atherosclerosis risk subtypes
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767999/
https://www.ncbi.nlm.nih.gov/pubmed/33381146
http://dx.doi.org/10.3389/fgene.2020.569572
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