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Sputum mast cell/basophil gene expression relates to inflammatory and clinical features of severe asthma

  • Author Footnotes
    ∗ These authors contributed equally.
    Natasha A. Winter
    Footnotes
    ∗ These authors contributed equally.
    Affiliations
    National Health and Medical Research Council Centre for Research Excellence in Severe Asthma, Newcastle, Australia

    The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, Australia

    School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia
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  • Author Footnotes
    ∗ These authors contributed equally.
    Ling Qin
    Footnotes
    ∗ These authors contributed equally.
    Affiliations
    Department of Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, China
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  • Peter G. Gibson
    Affiliations
    National Health and Medical Research Council Centre for Research Excellence in Severe Asthma, Newcastle, Australia

    The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, Australia

    School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia

    Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, Australia
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  • Vanessa M. McDonald
    Affiliations
    National Health and Medical Research Council Centre for Research Excellence in Severe Asthma, Newcastle, Australia

    The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, Australia

    School of Nursing and Midwifery, The University of Newcastle, Newcastle, Australia
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  • Katherine J. Baines
    Affiliations
    The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, Australia
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  • Jack Faulkner
    Affiliations
    Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, Australia
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  • Tiffany-Jane Evans
    Affiliations
    Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, Australia
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  • Michael Fricker
    Correspondence
    Corresponding author: Michael Fricker, BSc, PhD, Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Lot 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia.
    Affiliations
    National Health and Medical Research Council Centre for Research Excellence in Severe Asthma, Newcastle, Australia

    The Priority Research Centre for Health Lungs, The University of Newcastle, Newcastle, Australia

    School of Medicine and Public Health, The University of Newcastle, Newcastle, Australia
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally.
Published:February 17, 2021DOI:https://doi.org/10.1016/j.jaci.2021.01.033

      Background

      Mast cells (MCs) and basophils are important in asthma pathophysiology, however direct measurement is difficult, and clinical and inflammatory associations in severe asthma are poorly understood. Transcriptomic hallmarks of MCs/basophils may allow their measurement in sputum using gene expression.

      Objectives

      This study sought to develop and validate a sputum MC/basophil gene signature and investigate its relationship to inflammatory and clinical characteristics of severe asthma.

      Methods

      A total of 134 candidate MC/basophil genes (identified by the Immunological Genome Project Consortium) were screened in sputum microarray for differential expression among control subjects (n = 18), patients with eosinophilic (n = 29), and patients with noneosinophilic asthma (n = 30). Candidate genes were validated by confirming correlation of gene expression with flow cytometry-quantified sputum MCs and basophils in a separate asthma cohort (n = 20). The validated gene signature was measured in a severe asthma cohort (n = 81), and inflammatory and clinical associations were tested.

      Results

      Through microarray screening and subsequent validation, we found quantitative PCR gene expression of 8 targets correlated with sputum MCs/basophils: TPSAB1/TPSB2, CPA3, ENO2, GATA2, KIT, GPR56, HDC, SOCS2. In severe asthma, MC/basophil genes were associated with eosinophilic airway inflammation (GATA2, TPSB2, CPA3, GPR56, HDC, SOCS2), blood eosinophils (TPSB2, CPA3, GATA2, SOCS2, FCER1A, HDC), fractional exhaled NO (GATA2, SOCS2), decreased lung function (KIT, ENO2), and moderate exacerbation history (GATA2, SOCS2).

      Conclusions

      Quantitative PCR–based measures reflect varying sputum MC/basophil abundance, demonstrating associations of MCs/basophils with eosinophilic inflammation, spirometry and exacerbation history in severe asthma.

      Graphical abstract

      Key words

      Abbreviations used:

      ACQ (Asthma Control Questionnaire), AHR (Airway hyperresponsiveness), ASM (Airway smooth muscle), AUROC (Area under receiver operating characteristic), BR (Bronchodilator reversibility), EA (Eosinophilic asthma), Feno (Fractional exhaled nitric oxide), FVC (Forced vital capacity), LASSO (Least absolute shrinkage and selection operator), MC (Mast cell), NA (Neutrophilic asthma), NEA (Noneosinophilic asthma), NNA (Non-neutrophilic asthma), PBEs (Peripheral blood eosinophils), ppb (Parts per billion)
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