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Asthma
Original research
Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study
  1. Tatiana Karp1,2,
  2. Alen Faiz3,
  3. Jos van Nijnatten1,3,
  4. Huib A M Kerstjens1,2,
  5. Ilse Boudewijn1,2,
  6. Monica Kraft4,
  7. Judith M Vonk1,5,
  8. Martijn C Nawijn1,6,
  9. Irene H Heijink1,2,6,
  10. Bianca Beghé7,
  11. Klaus F Rabe8,
  12. Alberto Papi9,
  13. Chris Brightling10,
  14. Dave Singh11,
  15. Thys van der Molen1,12,
  16. Salman Siddiqui13,
  17. Stephanie Christenson14,
  18. Victor Guryev1,15,
  19. Maarten van den Berge1,2
  1. 1 Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center, Groningen, The Netherlands
  2. 2 Department of Pulmonary Diseases, University of Groningen, University Medical Center, Groningen, The Netherlands
  3. 3 Respiratory Bioinformatics and Molecular Biology, University of Technology Sydney, Ultimo, New South Wales, Australia
  4. 4 Samuel Bronfman Department of Medicine, Icahn School of Medicine, Mount Sinai Medical Center, New York, New York, USA
  5. 5 Department of Epidemiology, University of Groningen, University Medical Center, Groningen, The Netherlands
  6. 6 Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands
  7. 7 Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy
  8. 8 Department of Medicine, Christian Albrechts University Kiel, Kiel and LungenClinic, Grosshansdorf, Germany
  9. 9 Section of Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
  10. 10 The Institute for Lung Health, NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK
  11. 11 Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK
  12. 12 Department of General Practice and Elderly Care Medicine, University of Groningen, University Medical Center, Groningen, The Netherlands
  13. 13 Imperial College London National Heart and Lung Institute, London, UK
  14. 14 Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, San Francisco, California, USA
  15. 15 European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center, Groningen, The Netherlands
  1. Correspondence to Tatiana Karp; t.karp{at}rug.nl

Abstract

Introduction Asthma is an inflammatory airways disease encompassing multiple phenotypes and endotypes. Several studies suggested gene expression in nasal epithelium to serve as a proxy for bronchial epithelium, being a non-invasive approach to investigate lung diseases. We hypothesised that molecular differences in upper airway epithelium reflect asthma-associated differences in the lower airways and are associated with clinical expression of asthma.

Methods We analysed nasal epithelial gene expression data from 369 patients with asthma and 58 non-asthmatic controls from the Assessment of Small Airways Involvement in Asthma study. Unsupervised hierarchical clustering was performed on asthma-associated genes. Asthma-associated gene signatures were replicated in independent cohorts with nasal and bronchial brushes data by comparing Gene Set Variation Analysis scores between asthma patients and non-asthmatic controls.

Results We identified 67 higher expressed and 59 lower expressed genes in nasal epithelium from asthma patients compared with controls (false discovery rate<0.05), including CLCA1, CST1 and POSTN, genes well known to reflect asthma in bronchial airway epithelium. Hierarchical clustering revealed several molecular asthma endotypes with distinct clinical characteristics, including an endotype with higher blood and sputum eosinophils, high fractional exhaled nitric oxide, and more severe small airway dysfunction, as reflected by lower forced expiratory flow at 50%. In an independent cohort, we demonstrated that genes higher expressed in the nasal epithelium reflect asthma-associated changes in the lower airways.

Conclusion Our results show that the nasal epithelial gene expression profile reflects asthma-related processes in the lower airways. We suggest that nasal epithelium may be a useful non-invasive tool to identify asthma endotypes and may advance personalised management of the disease.

  • Asthma
  • Airway Epithelium
  • Asthma Genetics
  • Asthma Mechanisms

Data availability statement

Data are available on reasonable request. For code used in the manuscript, see https://github.com/TatiKarp/gene_expression_thorax.

https://doi.org/10.1136/thorax-2023-221230

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    Data availability statement

    Data are available on reasonable request. For code used in the manuscript, see https://github.com/TatiKarp/gene_expression_thorax.

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    Footnotes

    • VG and MvdB contributed equally.

    • Contributors TK, VG and MvdB were involved in drafting the design of this nasal gene expression study, data analysis and interpretation and drafted the first manuscript version. MK, BB, KFR, AP, CB, DS, TvdM, SS and SC were involved in designing the main ATLANTIS study and contributed to data interpretation and manuscript writing. AF, JvN, HAMK, IB, JMV, MCN and IHH were involved in interpretation of the results and manuscript writing. All authors reviewed the final version of the manuscript. MvdB is a guarantor.

    • Funding This study was supported by Dutch Ministry of Health through public–private partnership PPP program. The ATLANTIS study was sponsored by Chiesi Pharmaceuticals. No award/grant number.

    • Competing interests The ATLANTIS study is supported by Chiesi. MK has received grants or contracts or consulting fees or payment or honoraria or support for meetings from National Institutes of Health, American Lung Association, Synairgen, Janssen, Astra-Zeneca, Sanofi, Chiesi, GSK, Kinaset, Genentech, European Respiratory Society, has patents planned, issued or pending from CoFounder and Chief Medical Officer, RaeSedo, has participated on advisory boards for ALung DSMB and has received stock or stock options from Equity ownership in RaeSedo, and other financial or non-financial interests from Section Editor, UptoDate. MCN has received grants or contracts or support for meetings from Chan Zuckerberg Initiative, European commission, Lung Foundation Netherlands, Stichting Astma Bestrijding, Belgian Respiratory Society and has a leadership role in Lung Bionetwork of the Human Cell Atlas. IHH has received grants or contracts from Boehringer Ingelheim, Roche, Rousselot. BB has received payment or honoraria from AZ, GSK, Guidotti,Chiesi, Menarini. KFR has received payment or honoraria from Astra Zeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie, Roche Pharma, has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, Sanofi & Regeneron, and has a leadership role in German Center for Lung Research (DZL), German Chest Society (DGP), American Thoracic Society (ATS). AP has received grants or contracts or consulting fees from Chiesi, AstraZeneca, GSK, Sanofi, Agenzia Italiana del farmaco (AIFA), Novartis,

      Avillion, ELPEN Pharmaceuticals, has received payment or honoraria from Chiesi, AstraZeneca, GSK, Menarini, Novartis, Zambon, Mundipharma, Sanofi, Edmond Pharma, IQVIA, Avillion, ELPEN Pharmaceuticals, has participated on Advisory Board for Chiesi, AstraZeneca, GSK, MSD, Novartis, Sanofi, IQVIA, Avillion, ELPEN Pharmaceuticals. CB has received grants or contracts or consulting fees from GSK, AZ, Sanofi, Regeneron, Roche, Genentech, BI, Chiesi, Novartis, Mologic, Areteia. DS has received consulting fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GlaxoSmithKline, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance Biopharma, Verona Pharma. TvdM has received payment or honoraria or support for attending meetings from GSK, Chiesi. SS has received consulting fees or payment or honoraria from Chiesi, Astra Zeneca, GSK, Areteia therapeutics, CSL Behring, AZ, Medscape. SC has received grants or contracts or consulting fees from NIH, American Lung Association, Sanofi, Regeneron, GlaxoSmithKline, AstraZeneca, Glenmark Pharmaceuticals, Amgen, Axon Advisors, and has received payment or honoraria from Sanofi/Regeneron, MJH Holdings: Physicians’ Education Resource, UpToDate, Wolters Kluwer Health, GlaxoSmithKline, has received support for attending meeting from AstraZeneca, GlaxoSmithKline, Sanofi/Regeneron, has participated on advisory boards for anofi/Regeneron, AstraZeneca, GlaxoSmithKline, and has leadership or fiduciary role in American Thoracic Society. MvdB has received grants or contracts from GlaxxoSmithKline, Astra Zeneca, Novartis, Genentech, Roche.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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