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Lookup NU author(s): Dr James Lordan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023Background: 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.
Author(s): Zeng X, Qing J, Li C-M, Lu J, Yamawaki T, Hsu Y-H, Vander Lugt B, Hsu H, Busby J, McDowell PJ, Jackson DJ, Djukanovic R, Matthews JG, Arron JR, Bradding P, Brightling CE, Chaudhuri R, Choy DF, Cowan D, Fowler SJ, Hardman TC, Harrison T, Howarth P, Lordan J, Mansur AH, Menzies-Gow A, Pavord ID, Walker S, Woodcock A, Heaney LG
Publication type: Article
Publication status: Published
Journal: Journal of Allergy and Clinical Immunology
Year: 2023
Volume: 152
Issue: 4
Pages: 876-886
Print publication date: 01/10/2023
Online publication date: 11/06/2023
Acceptance date: 09/05/2023
Date deposited: 12/09/2023
ISSN (print): 0091-6749
ISSN (electronic): 1097-6825
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.jaci.2023.05.023
DOI: 10.1016/j.jaci.2023.05.023
PubMed id: 37315813
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