Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control

Xue Zeng, Jing Qing, 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 Aaron, Peter Bradding, Christopher E Brightling, Rekha Chaudhuri, David F Choy, SJ Fowler, Timothy C. Hardman, Peter Howarth, Adel MansurMenzies-Gow AN, I. Pavord, Samantha Walker, Ashley Woodcock, Liam Heaney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)876-886
Number of pages11
JournalJournal of Allergy and Clinical Immunology
Volume152
Issue number4
Early online date04 Oct 2023
DOIs
Publication statusPublished - Oct 2023

Keywords

  • Asthma
  • Transcriptomics

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