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Identification of disease comorbidity through hidden molecular mechanisms.

ABSTRACT: Despite multiple diseases co-occur, their underlying common molecular mechanisms remain elusive. Identification of comorbid diseases by considering the interactions between molecular components is a key to understand the underlying disease mechanisms. Here, we developed a novel approach utilizing both common disease-causing genes and underlying molecular pathways to identify comorbid diseases. Our approach enables the analysis of common pathologies shared by comorbid diseases through molecular interaction networks. We found that the integration of direct genetic sharing and indirect high-level molecular associations revealed significantly strong consistency with known comorbid diseases. In addition, neoplasm-related diseases showed high comorbidity patterns within themselves as well as with other diseases, indicating severe complications. This study demonstrated that molecular pathway information could be used to discover disease comorbidity and hidden biological mechanism to understand pathogenesis and provide new insight on disease pathology.

SUBMITTER: Ko Y

PROVIDER: S-EPMC5172201 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Identification of disease comorbidity through hidden molecular mechanisms.

Ko Younhee Y Cho Minah M Lee Jin-Sung JS Kim Jaebum J

Scientific reports 20161219

Despite multiple diseases co-occur, their underlying common molecular mechanisms remain elusive. Identification of comorbid diseases by considering the interactions between molecular components is a key to understand the underlying disease mechanisms. Here, we developed a novel approach utilizing both common disease-causing genes and underlying molecular pathways to identify comorbid diseases. Our approach enables the analysis of common pathologies shared by comorbid diseases through molecular i ...[more]

PMID: 27991583

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Project description:BackgroundThere is a complex interaction between chronic kidney disease (CKD) and ulcerative colitis (UC), but the pathophysiological mechanisms underlying the coexistence of CKD and UC are unclear. This study aimed to investigate the key molecules and pathways that may mediate the co-occurrence of CKD and UC through quantitative bioinformatics analysis based on a public RNA-sequencing database.MethodsThe discovery datasets of CKD (GSE66494) and UC (GSE4183), as well as validation datasets of CKD (GSE115857) and UC (GSE10616), were downloaded from the Gene Expression Omnibus (GEO) database. After identifying differentially expressed genes (DEGs) with GEO2R online tool, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for the DEGs were performed. Next, protein-protein interaction network was constructed with Search Tool for the Retrieval of Interacting Genes (STRING) and visualized by Cytoscape. Gene modules were identified by the plug-in MCODE and hub genes were screened using the plug-in CytoHubba. Then, correlation between immune cell infiltration and hub genes was analyzed, and the receiver operating characteristic curves were used to assess the predictive value of hub genes. Finally, immunostaining of human specimens was used to validate the relevant findings.ResultsA total of 462 common DEGs were identified and selected for further analyses. GO and KEGG enrichment analyses indicated that these DEGs were primarily enriched in immune- and inflammation-related pathways. Among them, the PI3K-Akt signaling pathway ranked top in both discovery and validation cohorts, and the key signal molecule phosphorylated Akt (p-Akt) was shown to be significantly overexpressed in human CKD kidneys and UC colons, and further elevated in CKD-UC comorbidity specimens. Moreover, nine candidate hub genes, including CXCL8, CCL2, CD44, ICAM1, IL1A, CXCR2, PTPRC, ITGAX, and CSF3, were identified, of which ICAM1 was validated as a common hub gene. Besides, immune infiltration analysis revealed that neutrophils, macrophages, and CD4+ T memory cells significantly accumulated in both diseases, and ICAM1 was remarkably associated with neutrophil infiltration. Furthermore, intercellular adhesion molecule1 (ICAM1)-mediated neutrophil infiltration was validated to be upregulated in kidney and colon biopsies of CKD and UC patients, and further increased in patients diagnosed with both CKD and UC. Finally, ICAM1 had shown critical value as a diagnostic marker for the co-occurrence of CKD and UC.ConclusionsOur study elucidated that immune response, PI3K-Akt signaling pathway, and ICAM1-mediated neutrophil infiltration might be the common pathogenesis of CKD and UC, and identified ICAM1 as a key potential biomarker and therapeutic target for the comorbidity of these two diseases.

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Identification of disease comorbidity through hidden molecular mechanisms.

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Identification of disease comorbidity through hidden molecular mechanisms.

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