• Jeannette Bigler, Michael Boedigheimer, Schofield James P R JPR 3 Centre for Biological Sciences, Southampton University, Southampton, United Kingdom., Paul J Skipp, Julie Corfield, Anthony Rowe, Ana R Sousa, Martin Timour, Lori Twehues, Xuguang Hu, Graham Roberts, Andrew A Welcher, Wen Yu, Diane Lefaudeux, Meulder Bertrand De B 10 European Institute for Systems Biology and Medicine, Centre National de la Recherche Scientifique, Lyon, France., Charles Auffray, Kian F Chung, Ian M Adcock, Peter J Sterk, Ratko Djukanović, and U-BIOPRED Study Group ‖.
• 1 Amgen Inc., Seattle, Washington.
• Am. J. Respir. Crit. Care Med. 2017 May 15; 195 (10): 1311-1320.

RationaleStratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy.ObjectivesTo 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.MethodsTranscriptomic 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.Measurements And Main ResultsA 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.ConclusionsBlood 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).

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