Year: 2023
Type: article
Abstract: BACKGROUND: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. OBJECTIVES: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. METHODS: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. RESULTS: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. CONCLUSIONS: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.
Authors: Xue Zeng, Jing Qing, Chi-Ming Li, Jiamiao Lu, Tracy Yamawaki, Yi-Hsiang Hsu, Bryan Vander Lugt, Hailing Hsu, John Busby, P.J. McDowell, David J. Jackson, Ratko Djukanovic, John G. Matthews, Joseph R. Arron, Peter Bradding, Christopher E. Brightling, Rekha Chaudhuri, David F. Choy, D. Cowan, S.J. Fowler, Timothy C. Hardman, Tim Harrison, Peter Howarth, James Lordan, A.H. Mansur, Andrew Menzies-Gow, Ian D. Pavord, Samantha Walker, Ashley Woodcock, Liam G. Heaney
Institutions: Amgen (United States), Queen's University Belfast, King's College London, NIHR Southampton Biomedical Research Centre, University of Southampton, 23andMe (United States), University of Leicester, NIHR Leicester Biomedical Research Centre, Gartnavel General Hospital, University of Glasgow, Genentech, NHS Greater Glasgow and Clyde, Stobhill Hospital, Manchester Academic Health Science Centre, University of Manchester, Manchester University NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, University of Nottingham, Newcastle upon Tyne Hospitals NHS Foundation Trust, University Hospitals Birmingham NHS Foundation Trust, Heartlands Hospital, University of Birmingham, Harefield Hospital, University of Oxford, Asthma + Lung UK, Asthma UK
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
Funders: Amgen, Medical Research Council
OpenAlex ID: W4380342594