Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma. Issue 5 (27th September 2021)

• Record Type: Journal Article
• Authors: Kho, Alvin T; McGeachie, Michael J; Li, Jiang; Chase, Robert P; Amr, Sami S; Hastie, Annette T; Hawkins, Gregory A; Li, Xingnan; Chupp, Geoffrey L; Meyers, Deborah A; Bleecker, Eugene R; Weiss, Scott T; Tantisira, Kelan G
• Is Part Of: Thorax. Volume 77:Issue 5(2022)
• Page Start: 452
• Page End: 460
• Publication Date: 2021-09-27
• Subjects: asthma pharmacology -- asthma; Chest -- Diseases -- Periodicals; Thorax; Chest -- Diseases; Periodicals; Periodicals; 617.54
• DOI: 10.1136/thoraxjnl-2020-215523
• Languages: English
• ISSNs: 0040-6376

Abstract

Abstract : 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.