Identification of molecular candidates of cilia-associated alterations in asthma

<bold>Introduction:</bold> Asthma is characterized by a chronic inflammation and airway remodeling. The functionality of the airway epithelium is altered suggesting a central role in the pathophysiology. Cilia-associated abnormalities have been reported in the airway epithelium of asthmatic patients but the mechanisms remain not elucidated. <bold>Objectives:</bold> This study investigates cilia-associated dysregulations in large cohorts of severe asthmatics (SA) to identify potential key molecular actors of airway remodeling. <bold>Methods:</bold> Transcriptomic data of epithelial bronchial brushing from three cohorts of SA patients were analysed: U-BIOPRED (GSE76226, n=105), SARP (GSE63142, n=81) and IMSA (GSE158752, n=42). We focused on the cilia-associated genes to highlight common differentially expressed genes (DEGs) in all three cohorts between non-asthmatic and SA groups. <bold>Results:</bold> Seventeen percent of all cilia-associated genes were significantly dysregulated between non-asthmatic and SA groups in each cohort (144±74 DEGs representing 17±9%, p<0.05), 17 were found in all three datasets. The six most dysregulated genes have been selected. Two were upregulated in SA: <italic>PHLDB2</italic> (13±9%, p<0.05) and <italic>NEK6</italic> (8±4%, p<0.05). Four were downregulated in SA: <italic>CDON</italic> (6±1%, p<0.05), <italic>SCNN1G</italic> (7±3%, p<0.05), <italic>GLI3</italic> (6±2%, p<0.01), <italic>PKD2</italic> (6±3%, p<0.05). <bold>Conclusion:</bold> The <italic>in silico</italic> meta-analysis of the cilia-associated transcriptomic signature allows to robustly identify several dysregulated genes in SA. These candidates will be localized <italic>ex vivo</italic> in lung resections and bronchial biopsies from non-asthmatic and asthmatic patients. Ultimately, <italic>in vitro</italic> modulation of these candidates will address a potential restoration of epithelial homeostasis in asthma.