Identification of Differentially Expressed Genes Associated with Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Approaches

摘要

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal cardiovascular disease event with significant morbidity and mortality. However, its potential molecular mechanisms and potential key genes have not been totally evaluated. The gene expression profile of GSE33463, including 30 individuals diagnosed with IPAH and 41 normal controls, was downloaded from Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified using limma package in R. Gene Ontology (GO) annotation, the Kyoto Encyclopedia of Genes and Genomes (KEGG) were carried out to get further insight into the possible functions of the identified DEGs. Then, the protein-protein interaction (PPI) network of all DEGs was constructed. Nodes with higher degree centrality (>= 10) were considered as hub proteins in the PPI network. Area under the curve (AUC) values obtained from the receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic effectiveness of hub genes in discriminating IPAH from normal individuals. Sixty-nine DEGs were identified, including 41 upregulated and 28 downregulated DEGs. The GO enrichment analysis indicated that genes were significantly enriched in oxygen carrier activity, oxygen binding, heme binding, molecular carrier activity, and antioxidant activity. KEGG pathway enrichment showed that genes were mainly involved in cytokine and cytokine receptor, Chemokine signaling pathway, interleukin-17 signaling pathway, and Toll-like receptor (TLR) signaling pathway. JUN, ALAS2, HBD, EPB42, TLR7, SLC4A1, and CXCR4 were identified as the hub genes nodes. The area under the ROC curve indicated that three hub genes have high diagnostic value in IPAH with AUC of 0.934 [95% confidence interval (CI): 0.849-0.979] in TLR7, 0.910 (95% CI: 0.818-0.965) in JUN, and 0.895 (95% CI: 0.800-0.955) in CXCR4. The identified candidate key genes and pathways help us understand the molecular mechanisms underlying the pathogenesis of IPAH. TLR7, JUN, and CXCR4 may be novel biomarkers in IPAH diagnosis.