ADAR-mediated editing of miR-200b-3p in airway cells is associated with moderate-to-severe asthma Magnaye KM(1), Naughton KA(1), Huffman J(1), Hogarth DK(2), Naureckas ET(2), White SR(2), Ober C(1) 1. Department of Human Genetics, University of Chicago, Chicago, IL 2. Department of Medicine, University of Chicago, Chicago, IL Asthma is a chronic lung disease characterized by persistent airway inflammation and bronchial hyperresponsiveness. Altered microRNA-mediated gene silencing in bronchial epithelial cells has been reported in asthma, yet microRNA adenosine to inosine (A-to-I) editing in asthma remains unexplored. We performed the first genome-wide analysis of ADAR-mediated microRNA editing using microRNA-seq in primary bronchial epithelial cells from 142 adult asthma cases and non-asthma controls. Of 19 A-to-I edited sites detected in these microRNAs, 16 were in seed regions. Four of the 16 edited sites were observed in >10 individuals and were tested for differential editing (% A-to-I) between groups. One site at position 5 of miR-200b-3p was edited less frequently in asthma cases compared to controls (P = 0.013). A-to-I editing of this site was then compared between asthma severity groups (mild, moderate and severe) based on lung function and medication use. The moderate (P = 0.037) and severe (P = 0.00031), but not mild (P = 0.77), asthma cases had significantly less A-to-I editing of the 5th position of miR-200b-3p compared to controls. Bioinformatic prediction revealed 232 in silico target genes of the edited miR-200b-3p, which were enriched for both IL-4 and interferon gamma signaling pathways and included the SOCS1 (suppressor of cytokine signaling 1) gene. SOCS1 was more highly expressed in moderate (P = 0.017) and severe (P = 0.0054) asthma cases compared to controls. Moreover, both miR-200b-3p editing and SOCS1 were associated with BAL eosinophil levels and an epithelial cell signature of Type 2 asthma. Overall, reduced ADAR-mediated editing of the 5th position of miR-200b-3p in lower airway cells from moderate-to-severe asthmatics may lead to overexpression of a centrally important negative regulator of cytokine signaling, SOCS1. We proposed ADAR-mediated editing as an epigenetic mechanism contributing to features of moderate-to-severe asthma in adulthood. Supported by U19 AI095230. KMM is supported by F31 HL143891.