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A severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts

A severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts
A severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts
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.
1073-449X
1-176
Bigler, J.
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Boedigheimer, M.
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Schofield, J.P.R.
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Skipp, P.J.
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Corfield, J.
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Rowe, A.
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Sousa, A.R.
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Timour, M.
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Twehues, L.
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Hu, X.
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Roberts, G.
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Welcher, A.A.
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Yu, W.
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Chung, K.F.
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Adcock, I.M.
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Sterk, P.J.
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Djukanovic, R.
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Bigler, J.
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Boedigheimer, M.
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Schofield, J.P.R.
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Skipp, P.J.
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Corfield, J.
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Rowe, A.
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Sousa, A.R.
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Timour, M.
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Twehues, L.
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Hu, X.
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Roberts, G.
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Welcher, A.A.
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Yu, W.
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Chung, K.F.
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Adcock, I.M.
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Sterk, P.J.
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Djukanovic, R.
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Bigler, J., Boedigheimer, M. and Schofield, J.P.R. et al. (2016) A severe asthma disease signature from gene expression profiling of peripheral blood from U-BIOPRED cohorts. American Journal of Respiratory and Critical Care Medicine, 1-176. (doi:10.1164/rccm.201604-0866OC). (PMID:27925796)

Record type: 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.

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Bigler - U-BIOPRED, AJRCCM.pdf - Accepted Manuscript
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Accepted/In Press date: 6 December 2016
e-pub ahead of print date: 7 December 2016
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 404059
URI: https://eprints.soton.ac.uk/id/eprint/404059
ISSN: 1073-449X
PURE UUID: 2cc7f5e9-a03d-4284-ac4f-f86776cad071
ORCID for P.J. Skipp: ORCID iD orcid.org/0000-0002-2995-2959
ORCID for R. Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612

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Date deposited: 20 Dec 2016 11:30
Last modified: 20 Jul 2019 05:32

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Contributors

Author: J. Bigler
Author: M. Boedigheimer
Author: J.P.R. Schofield
Author: P.J. Skipp ORCID iD
Author: J. Corfield
Author: A. Rowe
Author: A.R. Sousa
Author: M. Timour
Author: L. Twehues
Author: X. Hu
Author: G. Roberts
Author: A.A. Welcher
Author: W. Yu
Author: K.F. Chung
Author: I.M. Adcock
Author: P.J. Sterk
Author: R. Djukanovic ORCID iD

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