A severe asthma disease signature from gene expression profiling of eripheral blood from UBIOPRED cohorts

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Title: A severe asthma disease signature from gene expression profiling of eripheral blood from UBIOPRED cohorts
Author(s): Bigler, J
Boedigheimer, M
Schofield, JPR
Skipp, PJ
Corfield, J
Rowe, A
Sousa, AR
Timour, M
Twehues, L
Hu, X
Roberts, G
Welcher, AA
Yu, W
Chung, KF
Adcock, IM
Sterk, PJ
Djukanović, R
Item Type: Journal Article
Abstract: Rationale: Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy. Objectives: To determine the value of blood to identify transcriptional differences between clinically defined asthmatic and non-asthmatic groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences. Methods: Transcriptomics profiles were generated by microarray analysis of blood from 610 asthmatic and control participants in U-BIOPRED. Differentially expressed genes (DEGs) were identified by ANOVA, including covariates for RNA quality, gender, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis. Measurements and Main Results: 1693 genes were differentially expressed between severe asthmatics and non-asthmatics. The differences to non-asthmatics in non-smoking severe and mild/moderate asthmatics were significantly related (r=0.76), with a larger effect size in the severe asthmatics. The majority, but not all, differences were explained by differences in circulating immune cell populations. Pathway analysis showed an increase in chemotaxis, migration, and myeloid cell trafficking in severe asthmatics, decreased B lymphocyte development and hematopoietic progenitor cells and lymphoid organ hypoplasia. Cluster analysis of DEGs created subgroups among the severe asthmatics that differed in molecular responses to oral corticosteroids. Conclusions: Blood gene expression differences between clinically defined subgroups of asthmatics and non-asthmatic individuals as well as subgroups of severe asthma defined by transcript profiles show the value of blood in stratifying asthma patients and identifying molecular pathways for further study.
Publication Date: 7-Dec-2016
Date of Acceptance: 6-Dec-2016
URI: http://hdl.handle.net/10044/1/42697
DOI: https://dx.doi.org/10.1164/rccm.201604-0866OC
ISSN: 1535-4970
Publisher: American Thoracic Society
Start Page: 1311
End Page: 1320
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 195
Issue: 10
Copyright Statement: © 2016 by the American Thoracic Society.
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
biomarker
immune cell
microarray
EOSINOPHILIC ASTHMA
TRANSGLUTAMINASE 2
PHENOTYPES
MECHANISMS
MICROARRAY
DISCOVERY
CELLS
DIFFERENTIATION
DEXAMETHASONE
NEUTROPHILS
biomarker
immune cell
microarray
observational study
biomarker
immune cells
microarray
Respiratory System
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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