Microenvironment of ruptured cerebral aneurysms discovered using data driven analysis of gene expression.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
30
03
2019
accepted:
09
07
2019
entrez:
23
7
2019
pubmed:
23
7
2019
medline:
27
2
2020
Statut:
epublish
Résumé
It is well known that ruptured intracranial aneurysms are associated with substantial morbidity and mortality, yet our understanding of the genetic mechanisms of rupture remains poor. We hypothesize that applying novel techniques to the genetic analysis of aneurysmal tissue will yield key rupture-associated mechanisms and novel drug candidates for the prevention of rupture. We applied weighted gene co-expression networks (WGCNA) and population-specific gene expression analysis (PSEA) to transcriptomic data from 33 ruptured and unruptured aneurysm domes. Mechanisms were annotated using Gene Ontology, and gene network/population-specific expression levels correlated with rupture state. We then used computational drug repurposing to identify plausible drug candidates for the prevention of aneurysm rupture. Network analysis of bulk tissue identified multiple immune mechanisms to be associated with aneurysm rupture. Targeting these processes with computational drug repurposing revealed multiple candidates for preventing rupture including Btk inhibitors and modulators of hypoxia inducible factor. In the macrophage-specific analysis, we identify rupture-associated mechanisms MHCII antigen processing, cholesterol efflux, and keratan sulfate catabolism. These processes map well onto several of highly ranked drug candidates, providing further validation. Our results are the first to demonstrate population-specific expression levels and intracranial aneurysm rupture, and propose novel drug candidates based on network-based transcriptomics.
Sections du résumé
BACKGROUND
It is well known that ruptured intracranial aneurysms are associated with substantial morbidity and mortality, yet our understanding of the genetic mechanisms of rupture remains poor. We hypothesize that applying novel techniques to the genetic analysis of aneurysmal tissue will yield key rupture-associated mechanisms and novel drug candidates for the prevention of rupture.
METHODS
We applied weighted gene co-expression networks (WGCNA) and population-specific gene expression analysis (PSEA) to transcriptomic data from 33 ruptured and unruptured aneurysm domes. Mechanisms were annotated using Gene Ontology, and gene network/population-specific expression levels correlated with rupture state. We then used computational drug repurposing to identify plausible drug candidates for the prevention of aneurysm rupture.
RESULTS
Network analysis of bulk tissue identified multiple immune mechanisms to be associated with aneurysm rupture. Targeting these processes with computational drug repurposing revealed multiple candidates for preventing rupture including Btk inhibitors and modulators of hypoxia inducible factor. In the macrophage-specific analysis, we identify rupture-associated mechanisms MHCII antigen processing, cholesterol efflux, and keratan sulfate catabolism. These processes map well onto several of highly ranked drug candidates, providing further validation.
CONCLUSIONS
Our results are the first to demonstrate population-specific expression levels and intracranial aneurysm rupture, and propose novel drug candidates based on network-based transcriptomics.
Identifiants
pubmed: 31329646
doi: 10.1371/journal.pone.0220121
pii: PONE-D-19-09066
pmc: PMC6645676
doi:
Substances chimiques
HLA Antigens
0
Hypoxia-Inducible Factor 1
0
Keratan Sulfate
9056-36-4
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0220121Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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