Distinct Type 2-high Inflammation Associated Molecular Phenotypes of Chronic Rhinosinusitis with Nasal Polyps with Comorbid Asthma

Abstract

<jats:title>Abstract</jats:title> <jats:p>Background Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and comorbid asthma have more severe disease and are difficult to treat. However, the phenotypes especially the molecular phenotypes of CRSwNP with comorbid asthma (CRSwNP+AS) are not clear. This study aimed to investigate the molecular phenotypes associated with CRSwNP+AS. Methods Nasal tissues from patients with CRSwNP+AS, CRSwNP-alone and control subjects were assessed with infiltrated inflammatory cells and concentrations of total IgE, and performed whole-transcriptome sequencing. Differentially expressed mRNAs (DE-mRNAs) and lncRNAs (DE-lncRNAs) and their associated pathways were analyzed. The correlations between type 2 cytokines and local eosinophils, tissue IgE, and transcriptome signatures were evaluated. Results More local eosinophils infiltration and higher levels of total IgE were found in nasal tissues from CRSwNP+AS than from CRSwNP-alone. RNA sequencing analysis identified 1988 common DE-mRNAs, and 176 common DE-lncRNAs shared by CRSwNP+AS versus control and CRSwNP-alone versus control. Weighted gene coexpression network analysis (WGCNA) identified LINC01146 as hub lncRNA dysregulated in both subtypes of CRSwNP. We identified 968 DE-mRNAs and 312 DE-lncRNAs between CRSwNP+AS and CRSwNP-alone. Both pathway enrichment analysis and WGCNA indicated that the phenotypic traits of CRSwNP+AS were mainly associated with higher activities of arachidonic acid metabolism, Th2 cytokines related pathway and fibrinolysis pathway, and oppositely lower activities of IL-17 signaling pathway. We further showed that the expression of Th2 cytokines, IL5 and IL13, were positively correlated with local eosinophils infiltration, tissue IgE level, and the expression of DE-mRNAs that related to arachidonic acid metabolism. Moreover, WGCNA identified HK3-006 as hub lncRNA in yellow module that most positively correlated with phenotypic traits of CRSwNP+AS. Conclusions Patients with CRSwNP+AS have distinct type 2-high inflammation and its associated transcriptome signatures in nasal tissues compared to patients with CRSwNP alone.</jats:p>