Transcriptome analysis for the screening of hub genes and potential drugs in hypersensitivity pneumonitis

Abstract

Hypersensitivity pneumonitis (HP), an immune-mediated subtype of interstitial lung diseases (ILDs), is mediated by repetitive inhalation of certain antigens. Transcriptomic signatures, which provide insight into the genetic alterations associated with a disease, somehow remain obscure for HP. In this study, unique transcriptome fingerprints associated with the pathogenesis of HP were investigated using systems biology approach. Furthermore, the metabolic signatures identified in our earlier study, were correlated with the differentially expressed genes (DEGs) to explore the integrated pathways. Two datasets (GSE150910 and GSE19314) procured from the Gene Expression Omnibus repository were used to identify the DEGs of HP patients. The enriched biological processes, altered pathways and protein-protein interaction (PPI) network associated with the DEGs were determined. Based on topological algorithms, 12 hub genes were screened; among which chemokine (C-X-C motif) ligand 13 (CXCL13), CXCL9 and ribosomal protein large 36A (RPL36A) were identified as the top-ranked hub genes. The expression levels of these three candidate genes were experimentally validated in an HP patient cohort using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The findings indicated a trend similar to that of the bioinformatics observations. We integrated the metabolic signatures identified earlier with these hub genes and found glycolysis and phosphatidylinositol-3-kinase (PI3K/AKT) pathways to be impaired in these patients. Finally, the drug-gene interaction database DGIdb 4.0 indicated rituximab to be a promising drug for the management of HP. The present study is the first of its kind to combine bioinformatics and experimental data to identify and validate the genetic signatures and downstream pathways associated with HP. Our findings open up a new window to probe into the gene-metabolite crosstalk involved in the pathogenesis of HP and highlight promising therapeutic strategies.