Identification of pathways significantly associated with spondyloarthropathy/ankylosing spondylitis using the sub-pathway method

Abstract

The aim of the present study was to extract potential sub-pathway biomarkers for spondyloarthropathy (SpA)/ankylosing spondylitis (AS) using a sub-pathway strategy. SpA/AS-relevant data, reference pathways and long non-coding (lnc)RNA-micro (mi)RNA-mRNA interactions were downloaded. The seed pathways based on Kyoto Encyclopedia of Genes and Genomes pathways and the mRNAs in the co-expressed lncRNA-mRNA interactions were extracted. Sub-pathways regulated by lncRNA were selected after establishing condition-specific lncRNA competitively regulated pathways (LCRP) network. Significant sub-pathways were further identified using the attract method. These significant sub-pathways were evaluated in the other independent published AS microarray data (E-GEOD-25101) using in silico validation. In addition, to uncover SpA/AS-relevant lncRNAs, the degree analysis for all nodes in the LCRP network was conducted. A total of 35 lncRNAs, 131 mRNAs and 145 co-expressed interactions were identified. When entering these 131 mRNAs into the reference pathways, 82 seed pathways were extracted, which were transformed into undirected graphs, and the 35 lncRNAs were mapped to the pathway graphs to further establish the condition-specific LCRP network. Based on degree analysis, four hub lncRNAs were selected, including C14orf169, LINC00242, LINC00116 and LINC00482. It was identified that 35 lncRNAs competitively regulating sub-pathways were involved in 56 complete pathways. Among these, the top three sub-pathways were path: 04010_1, which was a subregion of the mitogen-activated protein kinase (MAPK) signaling pathway; path: 04062-1, an important subregion in the chemokine signaling pathway; and path: 04066-2, was a part of HIF-1 signaling pathway. Furthermore, it was validated consistently in the separate microarray data set E-GEOD-25101. Cancer-associated pathways and hub node C14orf169 were identified in validation. Sub-pathways, including the MAPK signaling pathway and chemokine signaling pathway, and hub lncRNA (C14orf169) may serve important roles in SpA/AS.