A severe asthma disease signature from gene expression profiling of eripheral blood from UBIOPRED cohorts
File(s)Blue-201604-0866OC Accepted Version.pdf (11.91 MB)
Accepted version
Author(s)
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.
Date Issued
2017-05-15
Date Acceptance
2016-12-06
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.
Sponsor
National Institute for Health Research
Medical Research Council (MRC)
Medical Research Council (MRC)
National Institute for Health Research
Grant Number
NF-SI-0509-10080
G1000758
G1000758
NF-SI-0515-10016
Subjects
observational study
biomarker
immune cells
microarray
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
HEALTH
CELLS
DIFFERENTIATION
DEXAMETHASONE
biomarker
immune cell
microarray
Adrenal Cortex Hormones
Adult
Asthma
Cluster Analysis
Cohort Studies
Europe
Female
Gene Expression Profiling
Humans
Male
Microarray Analysis
Middle Aged
Prospective Studies
Severity of Illness Index
Transcriptome
U-BIOPRED Study Group ‖
Humans
Asthma
Adrenal Cortex Hormones
Microarray Analysis
Severity of Illness Index
Cluster Analysis
Cohort Studies
Prospective Studies
Gene Expression Profiling
Adult
Middle Aged
Europe
Female
Male
Transcriptome
11 Medical and Health Sciences
Respiratory System
Publication Status
Published
Date Publish Online
2016-12-07