Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma
Year: 2021
Type: article
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 (withouta prioriclinical 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, FEV1change (Kendall tau-b R=−0.333 (−0.592 to −0.012)) and follow-up FEV1albuterol 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 FEV1change 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.
Source: Thorax
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Mechanistic insights into asthma pathogenesis through the integration of asthma genes, risk exposures, and metabolomics, Longitudinal Phenomics and Genetics of Severe Asthma, Pharmacogenetics of Asthma Treatment, Integrative Metabolomics of Asthma Severity, PrecISE Network: ADAPT (Advancing Severe Asthma Precision Therapy), Systems Biology to Identify Biomarkers of Neonatal Vaccine Immunogenicity, Systems Biology of Airway Disease, DISEASE AND HEALTH: ASTHMA RESILIENCE THROUGH MICRORNA ATTRIBUTES (DHARMA), MICRORNAS IN CIRCULATION: ONTOLOGIES OF ASTHMA SEVERITY AND TREATMENT (MICROCOAST), Asthma Exacerbations and MicroRNA prediction: Treatment Response in an Underserved Ethnicity (AEM-TRUE), MICRORNAS AND EARLY LIFE EXPOSURES IN THE DEVELOPMENTAL ORIGIN OF ASTHMA, G572337302, INTEGRATIVE PHARMACOGENOMICS OF LEUKOTRIENE INHIBITION IN ASTHMA, Genomics and Pharmacogenomics of Symptoms in Asthma, Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping, Omic Determinants of Longitudinal Lung Function in Asthma
OpenAlex ID: W3201807608