The NOVELTY nasal transcriptome identifies mechanisms in asthma and COPD exacerbators

<bold>Background:</bold> Asthma and COPD are two prevalent and complex diseases in which exacerbations occur. In patients with asthma or COPD from NOVELTY (<ext-link>NCT02760329</ext-link>), we explored the nasal gene expression associated with exacerbation risk. <bold>Methods:</bold> Nasal RNAseq was performed on 208 patients: 122 with asthma (58.7%) and 86 with COPD (41.3%). For each physician-assigned diagnosis, DESeq2 was used to identify genes associated with the risk of having ≥2 moderate or severe exacerbations during 1 year of follow-up (i.e. exacerbators), adjusting for sex and sampling season. Independent component analysis (ICA) was used to identify sets of genes from independent latent factors (‘metagenes’) associated with the number of exacerbations. <bold>Results:</bold> Between exacerbators and non-exacerbators, 25 and 450 differentially expressed genes were observed in asthma and COPD exacerbators, respectively; only 3 genes were common (DAAM2, ACSL1 and IL1R2). However, using ICA that accounts for the contribution of a set of genes, we identified 2 metagenes significantly (FDR<0.05) associated with the number of exacerbations in COPD (M#0 and M#31) and 5 in asthma (M#5, M#23, M#25, M#27 and M#29). In patients with COPD, exacerbation metagenes were associated with neutrophil degranulation and leukocyte migration genes, while in patients with asthma, exacerbation metagenes were associated with arachidonic acid metabolism, collagen and elastin catabolism, extracellular matrix organisation and humoral antimicrobial defence processes. <bold>Conclusion</bold>: These results suggest that, in the real-world setting, asthma and COPD exacerbators can have distinct molecular mechanisms, which can be identified using non-invasive nasal airway sampling.