TY - JOUR T1 - Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma JF - Thorax JO - Thorax DO - 10.1136/thoraxjnl-2020-215523 SP - thoraxjnl-2020-215523 AU - Alvin T Kho AU - Michael J McGeachie AU - Jiang Li AU - Robert P Chase AU - Sami S Amr AU - Annette T Hastie AU - Gregory A Hawkins AU - Xingnan Li AU - Geoffrey L Chupp AU - Deborah A Meyers AU - Eugene R Bleecker AU - Scott T Weiss AU - Kelan G Tantisira Y1 - 2021/09/26 UR - http://thorax.bmj.com/content/early/2021/09/26/thoraxjnl-2020-215523.abstract N2 - Introduction Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies.Methods We applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6–8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables.Results PC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV1 change (Kendall tau-b R=−0.333 (−0.592 to −0.012)) and follow-up FEV1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset.Conclusions Transcriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data used in this study will be publicly available on NCBI GEO GSE184433 upon publication. ER -