ASSESSING THE UNIFIED AIRWAY HYPOTHESIS IN CHILDREN VIA TRANSCRIPTIONAL PROFILING OF THE AIRWAY EPITHELIUM

Background Emerging evidence suggests that disease vulnerability is expressed throughout the airways; the so-called “unified airway hypothesis” but the evidence to support this is predominantly indirect. Objectives To establish the transcriptomic profiles of the upper and lower airway and determine their level of similarity irrespective of airway symptoms (wheeze) and allergy. Methods We performed RNA-sequencing on upper and lower airway epithelial cells from 63 children with or without wheeze and accompanying atopy, utilizing differential gene expression and gene co-expression analyses to determine transcriptional similarity. Results We observed ∼91% homology in the expressed genes between the two sites. When co-expressed genes were grouped into modules relating to biological functions, all were found to be conserved between the two regions, resulting in a consensus network containing 16 modules associated with ribosomal function, metabolism, gene expression, mitochondrial activity and anti-viral responses through interferon activity. Although symptom associated gene expression changes were more prominent in the lower airway, they were reflected in nasal epithelium and included; IL1RL1, PTGS1, CCL26 and POSTN. Through network analysis we identified a cluster of co-expressed genes associated with atopic-wheeze in the lower airway, which could equally distinguish atopic and non-atopic phenotypes in upper airway samples. Conclusions We show that the upper and lower airway are significantly conserved in their transcriptional composition, and that variations associated with disease are present in both nasal and tracheal epithelium. Findings from this study supporting a unified airway imply that clinical insight regarding the lower airway in health and disease can be gained from studying the nasal epithelium.