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Randomized Controlled Trial
. 2023 Oct;152(4):876-886.
doi: 10.1016/j.jaci.2023.05.023. Epub 2023 Jun 12.

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

Xue Zeng  1 , Jing Qing  1 , Chi-Ming Li  1 , Jiamiao Lu  1 , Tracy Yamawaki  1 , Yi-Hsiang Hsu  2 , Bryan Vander Lugt  1 , Hailing Hsu  3 , John Busby  4 , P J McDowell  4 , David J Jackson  5 , Ratko Djukanovic  6 , John G Matthews  7 , Joseph R Arron  7 , Peter Bradding  8 , Christopher E Brightling  8 , Rekha Chaudhuri  9 , David F Choy  10 , D Cowan  11 , S J Fowler  12 , Timothy C Hardman  13 , Tim Harrison  14 , Peter Howarth  6 , James Lordan  15 , A H Mansur  16 , Andrew Menzies-Gow  17 , Ian D Pavord  18 , Samantha Walker  19 , Ashley Woodcock  12 , Liam G Heaney  20 ; investigators for the UK MRC Refractory Asthma Stratification Program (RASP-UK)
Affiliations
Randomized Controlled Trial

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

Xue Zeng et al. J Allergy Clin Immunol. 2023 Oct.

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.

Keywords: Severe asthma; T2-cytokine; T2-low; biomarker; oral corticosteroids; whole blood transcriptome.

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