GSEA and co-expression network approach to identify molecular processes affected in Porto-sinusoidal Vascular Disease

Abstract

AbstractBackground & AimsPorto-sinusoidal vascular disease (PSVD) is a complex rare liver disease characterized by the absence of cirrhosis with or without the presence of portal hypertension or histological lesions. Given the knowledge gaps in the mechanisms involved in this disease with unknown etiology, we used omics-based approaches to further elucidate the pathways affected in PSVD thereby facilitating an improvement in the prognosis, diagnosis, and treatment options for these patients.MethodsFor this study we used a microarray dataset (GEO:GSE77627) of 11 histologically normal liver biopsies and 18 PSVD liver biopsies. First approach, differential gene expression analysis was performed and next gene set enrichment analysis was used to identify enriched biological pathways. A network-based approach of weighted gene coexpression analysis was implemented to identify modules of interconnected genes related to the diagnosis of the patients. We further studied the pathways enriched in these modules to allow identification of processes explaining the mechanisms involved in PSVD, while the gene network could also be used to understand the connections between the processes.ResultsGene set enrichment of differentially expressed genes indicated an increase in signaling and cell-cycle related processes and a decrease in metabolism-related processes. Coexpression network and module analysis further validated these results by elucidating connections between GPCR signaling, energy metabolism and cell-migration related processes. Furthermore, an additional connection between fibrin clot formation processes, inflammation and immune response and cell cycle and respiration processes was identified.ConclusionSignaling and metabolism-related processes are deregulated in PSVD patients. Furthermore, two triangular connections (GPCR signaling-energy metabolism-cell migration and fibrin-clot formation-inflammation and immune response - cell -cycle and respiration) revealed unique unknown connections involved in PSVD etiology.Impact and implicationsPSVD is a complex rare liver disease with significant knowledge gaps in the understanding of the mechanisms and pathways affected at the molecular level. In this study, we use publicly available transcriptomics data and bioinformatics tools to elucidate pathways affected in PSVD patients. In this study, we found potential novel relations between pathways with the two triangular connections (GPCR signaling-energy metabolism-cell migration and fibrin-clot formation-inflammation and immune response - cell -cycle and respiration). These newfound connections between pathways might shed light on the etiology of this disease and help researchers develop effective diagnosis and prognosis for patients suffering from PSVD.