Microenvironment of ruptured cerebral aneurysms discovered using data driven analysis of gene expression

Abstract

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.

Transcriptomic Studies on Intracranial Aneurysms

“…Along with the development of bioinformatic tools appeared a new type of study presenting re-analyzed data from available datasets, including expression data from the Gene Expression Omnibus (GEO). Approximately one third of these published secondary analyses utilized a single dataset [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ] and two thirds leveraged data from two to eight datasets [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. These studies did not provide any new additional clinical data but rather aimed to deepen the insight into molecular mechanisms of the IA pathophysiology by revealing key regulatory networks and interactions between investigated molecules.…”

“…In some of these studies, specific areas of interest were predefined, such as: epithelial–mesenchymal transition [ 78 ], endoplasmic reticulum stress [ 81 ], immune environment [ 79 , 83 ], or ferroptosis [ 84 , 85 ]. In three studies, an attempt was made to identify potential therapeutic targets [ 71 , 82 , 83 ]. Sun et al investigated expression profiles and networks in various aneurysms, including thoracic and abdominal aorta aneurysms [ 77 ].…”

Epithelial–mesenchymal transition related genes in unruptured aneurysms identified through weighted gene coexpression network analysis

“…Nakaoka et al 8 identified therapeutic targets for unruptured IAs. Landry et al 9 demonstrated for the first time the immune mechanism of IA rupture and new drug candidates. Whether EMT plays an important role in the progression of aneurysm is worthy of further exploration.…”

Identification and validation of key genes mediating intracranial aneurysm rupture by weighted correlation network analysis

“…Alongside crucial genes, Bo et al identified several crucial miRNAs as mediators of IA pathogenesis (19). Additionally, Landry et al combined WGCNA and population-specific gene expression analysis (PSEA) to analyze the microenvironment associated with ruptured IA (20). Although WGCNA has partially elucidated the pathogenesis of IA, the crucial genes mediating the rupture of IA require exploration.…”