Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study

Tatiana Karp; Alen Faiz; Jos van Nijnatten; Huib A M Kerstjens; Ilse Boudewijn; Monica Kraft; Judith M Vonk; Martijn C Nawijn; Irene H Heijink; Bianca Beghé; Klaus F Rabe; Alberto Papi; Chris Brightling; Dave Singh; Thys van der Molen; Salman Siddiqui; Stephanie Christenson; Victor Guryev; Maarten van den Berge

doi:10.1136/thorax-2023-221230

Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study

Thorax. 2024 Sep 18;79(10):905-914. doi: 10.1136/thorax-2023-221230.

Authors

Tatiana Karp^{1

2}, Alen Faiz³, Jos van Nijnatten^{4

3}, Huib A M Kerstjens^{4

2}, Ilse Boudewijn^{4

2}, Monica Kraft⁵, Judith M Vonk^{4

6}, Martijn C Nawijn^{4

7}, Irene H Heijink^{4

2

7}, Bianca Beghé⁸, Klaus F Rabe⁹, Alberto Papi¹⁰, Chris Brightling¹¹, Dave Singh¹², Thys van der Molen^{4

13}, Salman Siddiqui¹⁴, Stephanie Christenson¹⁵, Victor Guryev^#^{4

16}, Maarten van den Berge^#^{4

2}

Affiliations

¹ Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center, Groningen, The Netherlands t.karp@rug.nl.
² Department of Pulmonary Diseases, University of Groningen, University Medical Center, Groningen, The Netherlands.
³ Respiratory Bioinformatics and Molecular Biology, University of Technology Sydney, Ultimo, New South Wales, Australia.
⁴ Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center, Groningen, The Netherlands.
⁵ Samuel Bronfman Department of Medicine, Icahn School of Medicine, Mount Sinai Medical Center, New York, New York, USA.
⁶ Department of Epidemiology, University of Groningen, University Medical Center, Groningen, The Netherlands.
⁷ Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands.
⁸ Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy.
⁹ Department of Medicine, Christian Albrechts University Kiel, Kiel and LungenClinic, Grosshansdorf, Germany.
¹⁰ Section of Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.
¹¹ The Institute for Lung Health, NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
¹² Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK.
¹³ Department of General Practice and Elderly Care Medicine, University of Groningen, University Medical Center, Groningen, The Netherlands.
¹⁴ Imperial College London National Heart and Lung Institute, London, UK.
¹⁵ Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, San Francisco, California, USA.
¹⁶ European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center, Groningen, The Netherlands.

^# Contributed equally.

PMID: 39009441
DOI: 10.1136/thorax-2023-221230

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.

Keywords: Airway Epithelium; Asthma; Asthma Genetics; Asthma Mechanisms.

MeSH terms

Adult
Asthma* / genetics
Asthma* / metabolism
Case-Control Studies
Female
Gene Expression
Humans
Male
Middle Aged
Nasal Mucosa* / metabolism
Phenotype