title: A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts.
abstract: Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy.
  
  
  
  To determine the value of blood analysis to identify transcriptional differences between clinically defined asthma and nonasthma groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences.
  
  
  
  Transcriptomic profiles were generated by microarray analysis of blood from 610 patients with asthma and control participants in the U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) study. Differentially expressed genes (DEGs) were identified by analysis of variance, including covariates for RNA quality, sex, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis.
  
  
  
  A total of 1,693 genes were differentially expressed between patients with severe asthma and participants without asthma. The differences from participants without asthma in the nonsmoking severe asthma and mild/moderate asthma subgroups were significantly related (r = 0.76), with a larger effect size in the severe asthma group. The majority of, 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 patients with severe asthma, decreased B-lymphocyte development and hematopoietic progenitor cells, and lymphoid organ hypoplasia. Cluster analysis of DEGs led to the creation of subgroups among the patients with severe asthma who differed in molecular responses to oral corticosteroids.
  
  
  
  Blood gene expression differences between clinically defined subgroups of patients with asthma and individuals without asthma, as well as subgroups of patients with severe asthma defined by transcript profiles, show the value of blood analysis in stratifying patients with asthma and identifying molecular pathways for further study. Clinical trial registered with www.clinicaltrials.gov (NCT01982162).
authors.affiliation: 1 Amgen Inc., Seattle, Washington.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.affiliation: 2 Amgen Inc., Thousand Oaks, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Boedigheimer
authors.affiliation: 3 Centre for Biological Sciences, Southampton University, Southampton, United Kingdom.
authors.forename: James P R
authors.initials: JPR
authors.lastname: Schofield
authors.affiliation: 3 Centre for Biological Sciences, Southampton University, Southampton, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Skipp
authors.affiliation: 4 AstraZeneca R&D, Molndal, Sweden.|5 Areteva R&D, Nottingham, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Corfield
authors.affiliation: 6 Janssen Research and Development, High Wycombe, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rowe
authors.affiliation: 7 Respiratory Therapeutic Unit, GSK, Stockley Park, United Kingdom.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Sousa
authors.affiliation: 1 Amgen Inc., Seattle, Washington.
authors.forename: Martin
authors.initials: M
authors.lastname: Timour
authors.affiliation: 2 Amgen Inc., Thousand Oaks, California.
authors.forename: Lori
authors.initials: L
authors.lastname: Twehues
authors.affiliation: 8 Amgen Inc., South San Francisco, California.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Hu
authors.affiliation: 9 Respiratory Biomedical Research Unit, Faculty of Medicine, University Hospital Southampton, Southampton, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Roberts
authors.affiliation: 2 Amgen Inc., Thousand Oaks, California.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Welcher
authors.affiliation: 1 Amgen Inc., Seattle, Washington.
authors.forename: Wen
authors.initials: W
authors.lastname: Yu
authors.affiliation: 10 European Institute for Systems Biology and Medicine, Centre National de la Recherche Scientifique, Lyon, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Lefaudeux
authors.affiliation: 10 European Institute for Systems Biology and Medicine, Centre National de la Recherche Scientifique, Lyon, France.
authors.forename: Bertrand De
authors.initials: B
authors.lastname: Meulder
authors.affiliation: 10 European Institute for Systems Biology and Medicine, Centre National de la Recherche Scientifique, Lyon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Auffray
authors.affiliation: 11 National Heart & Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom; and.
authors.forename: Kian F
authors.initials: KF
authors.lastname: Chung
authors.affiliation: 11 National Heart & Lung Institute, Imperial College & Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom; and.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: 12 Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sterk
authors.affiliation: 9 Respiratory Biomedical Research Unit, Faculty of Medicine, University Hospital Southampton, Southampton, United Kingdom.
authors.forename: Ratko
authors.initials: R
authors.lastname: Djukanović
mesh_terms: D000305:Adrenal Cortex Hormones / Q000097:blood / Q000627:therapeutic use*; D000328:Adult; D001249:Asthma / Q000097:blood* / Q000188:drug therapy*; D016000:Cluster Analysis; D015331:Cohort Studies; D005060:Europe; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008297:Male; D046228:Microarray Analysis / Q000706:statistics & numerical data; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000305:Adrenal Cortex Hormones
keywords: biomarker; immune cell; microarray