Nasal airway epithelium differentiates between asthma and healthy subjects and identifies clinically relevant asthma endotypes

Abstract

<b>Introduction:</b> Asthma is a heterogeneous inflammatory disease of the airways that comprises multiple endotypes. Previous studies suggest that the nasal epithelium mirrors the changes in the lower airways of asthma patients. Accordingly, we hypothesize that upper airway epithelium is biologically active and reflects lower airway alterations in asthma. <b>Methods:</b> Differential gene expression analysis of nasal brushes was performed in 369 asthmatics with different severities and 58 healthy controls from the ATLANTIS study. Replication was assessed in an independent cohort with nasal brushes from 55 asthmatics and 47 controls. Cell type deconvolution was used to evaluate cell type proportions in bulk RNA-seq data. <b>Results:</b> We identified 67 up- and 59 downregulated genes in nasal epithelium from asthmatics compared to controls (FDR &lt; 0.05). Gene set variation scores across up-and downregulated genes in asthmatic versus healthy controls were replicated in the independent cohort. Among up-regulated genes, we found known asthma genes such as CLCA1, POSTN, and CST1, previously identified to be associated with asthma in bronchial epithelium. Hierarchical clustering revealed asthma endotypes with distinct clinical characteristics, including eosinophilic and non-eosinophilic asthma. Proportions of goblet and ciliated cells were not significantly different between the phenotypes, suggesting that cell activation rather than cell type composition is driving differences between asthma phenotypes. <b>Conclusion:</b> Nasal epithelial gene expression reflects asthma-associated changes observed in the lower airways and may be used as a non-invasive tool to investigate asthma endotypes.