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

被引：9

作者：

Zeng, Xue ^{[1
]}

Qing, Jing ^{[1
]}

Li, Chi-Ming ^{[1
]}

Lu, Jiamiao

Yamawaki, Tracy ^{[1
]}

Hsu, Yi-Hsiang ^{[2
]}

Vander Lugt, Bryan ^{[1
]}

Hsu, Hailing ^{[3
]}

Busby, John ^{[4
]}

McDowell, P. J. ^{[4
]}

Jackson, David J. ^{[5
,6
]}

Djukanovic, Ratko ^{[7
]}

Matthews, John G. ^{[8
]}

Arron, Joseph R. ^{[8
]}

Bradding, Peter ^{[9
,10
]}

Brightling, Christopher E. ^{[9
,10
]}

Chaudhuri, Rekha ^{[11
,12
]}

Choy, David F. ^{[13
]}

Cowan, D. ^{[14
]}

Fowler, S. J. ^{[15
]}

Hardman, Timothy C. ^{[18
]}

Harrison, Tim ^{[19
]}

Howarth, Peter ^{[7
]}

Lordan, James ^{[20
]}

Mansur, A. H. ^{[21
]}

Menzies-Gow, Andrew ^{[22
]}

Pavord, Ian D. ^{[23
]}

Walker, Samantha ^{[24
]}

Woodcock, Ashley ^{[15
,16
,17
]}

Heaney, Liam G. ^{[4
]}

机构：

[1] Amgen Inc, Amgen Res, South San Francisco, CA USA

[2] Amgen Inc, Amgen Res, Cambridge, MA USA

[3] Amgen Inc, Amgen Res, Thousand Oaks, CA USA

[4] Queens Univ, Sch Med Dent & Biomed Sci, Wellcome Wolfson Ctr Expt Med, Belfast, North Ireland

[5] Kings Coll London, Guys & St Thomas NHS Trust, London, England

[6] Kings Coll London, Dept Asthma Allergy & Lung Biol, Fac Life Sci & Med, London, England

[7] NIHR Southampton Biomed Res Ctr, Sch Clin & Expt Sci, Southampton, England

[8] 23andMe, Sunnyvale, CA USA

[9] Univ Leicester, Inst Lung Hlth, Dept Resp Sci, Leicester, England

[10] Univ Leicester, Leicester NIHR Biomed Res Ctr, Leicester, England

[11] Gartnavel Royal Hosp, Glasgow, Scotland

[12] Univ Glasgow, Glasgow, Scotland

[13] Genentech Inc, South San Francisco, CA USA

[14] NHS Greater Glasgow & Clyde, Stobhill Hosp, Glasgow, Scotland

[15] Univ Manchester, Sch Biol Sci, Div Infect Immun & Resp Med, Manchester, England

[16] Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, England

[17] Manchester Univ Hosp NHS Fdn Trust, NIHR Manchester Biomed Res Ctr, Manchester, England

[18] Niche Sci & Technol Ltd, Richmond, Surrey, England

[19] Univ Nottingham, Nottingham Resp NIHR Biomed Res Ctr, Nottingham, England

[20] Newcastle upon Tyne NHS Fdn Trust, Newcastle Upon Tyne, England

[21] Univ Hosp Birmingham NHS Fdn Trust, Univ Birmingham & Heartlands Hosp, Birmingham, England

[22] Royal Brompton & Harefield Hosp, London, England

[23] Univ Oxford, Oxford Resp NIHR BRC, Nuffield Dept Med, Oxford, England

[24] Asthma UK & British Lung Fdn Partnership, London, England

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2023年 / 152卷 / 04期

关键词：

Severe asthma; whole blood transcriptome; biomarker; T2-low; T2-cytokine; oral corticosteroids; LEYDEN CRYSTAL PROTEIN; DOUBLE-BLIND; EXPRESSION;

D O I：

10.1016/j.jaci.2023.05.023

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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. (J Allergy Clin Immunol 2023;152:876-86.)

引用

页码：876 / 886

页数：11

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