Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma.
Thorax
; 77(5): 452-460, 2022 05.
Article
em En
| MEDLINE
| ID: mdl-34580195
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Asma
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Eosinófilos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article