Biomarkers Identification And Gene Expression Analysis In Allergic Rhinitis And Non-allergic Rhinitis

Background:Allergic rhinitis(AR)is the most common chronic inflammatory disease of nasal mucosa,characterized by IgE-mediated Th2 immune response.Nonallergic rhinitis(NAR)is a clinically excluded diagnosis with nasal hyperreactivity symptoms but presents a negative atopic test.NAR exhibits similar nasal symptoms to those of AR but its gene expression and relationship with AR are unclear.Objectives:The aim of this study was to observe and compare epithelial gene expression in patients with allergic rhinitis and nonallergic rhinitis based on multiple microarray data,which might be helpful for the diagnosis and treatment of different types of rhinitis.Methods:Four gene expression datasets containing AR and healthy control were downloaded from the GEO database.The Robust Rank Aggreg analysis was used to detect differentially expressed genes(DEGs).Weighted coexpression network analysis was used to determine the key modules with high relevance to AR,which combined with DEGs to identify the differential coexpression genes(co-DEGs).Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were performed to explore potential biological mechanisms.Cytoscape technology was used to construct the protein interaction network based on STRING database for identifing the hub genes.Then the iRegulon plug-in was used to explore the upstream regulator of hub genes.Nasal brushing epithelial cells of AR,NAR,and control were used to validate hub genes by RT-PCR.The gene expression similarities and differences in AR and NAR were also compared.Furthermore,patients were followed and the clinical implications of validated genes were analyzed.Results:34 DEGs were screened by RRA analysis,two AR related modules were identified by WGCNA,and 17 hub genes were screened by combining RRA and WGCNA.GO and KEGG results showed that DEGs was mainly related to immune response regulation,peptidase activity and epithelial cell maintenance,brown module was mainly related cell membrane system and substance transport metabolism,and magenta module was related to protease activity,cell migration,chloride ion transport and salivation.PPI network and Cytoscape plug-ins were used to screen and score 10 hub genes,namely POSTN,CDH26,CCL26,CLC,CPA4,CP A3,CST1,SERPINB2,HDC,FETUB.Except for CCL26,CLC and CPA4,other 7 genes were regulated by CUX2.PCR results showed that all 10 genes were significantly increased in AR.In addition to FETUB,the expressions of other 9 genes were also significantly increased in the NAR group.The expression of CLC in AR group was significantly higher than that in NAR group.The expression of SERPINB2 was significantly higher in mixed allergic rhinitis than in seasonal AR.There was a significant and very weak positive correlation between CCL26 and the duration of allergic rhinitis,and a significant positive correlation between CLC and the severity of allergic rhinitis.The expression of CLC in moderate-severe AR was significantly higher than that in mild AR.ROC curve showed that CST1,CLC and CPA3 had good diagnostic efficiency for AR.Meanwhile,POSTN、CLC and CP A3 had good predictive ability for NAR.Conclusion:The expression of genes in the nasal epithelium of AR and NAR showed great similarity,and most genes were related to Th2 inflammatory response.FETUB and CLC might show a good diagnostic value in distinguishing AR and NAR.SERPINB2 may be a potential biomarker for identifying AR allergen types.