Substituting a single nucleotide in the gene coding for the nicotinic acetylcholine receptor can lead to functional changes in airway cells and result in symptoms similar to COPD, independent of smoking, new research1 has found.

Chronic obstructive pulmonary disease (COPD) is a progressive chronic respiratory disease characterized by permanently obstructed airways. Symptoms include a chronic cough, sputum and breathing difficulties, which intensify over the course of several years and eventually become debilitating.

COPD-like remodeling in human airway epithelium

Scheme highlighting the experimental systems. Credit: Routhier, J., Pons, S., Freidja, M.L. et al, CC-BY

In 2019, the WHO ranked COPD third among the leading global causes of death, behind heart disease and stroke. However, some mechanisms of this debilitating chronic respiratory disease are yet to be identified.

CHRNA5 Gene Nucleotide

Earlier human genome-wide association studies have linked COPD to genes located on chromosome 15 coding for subunits of the nicotinic acetylcholine receptor (nAChR)2. In this new study, scientists at the Institut Pasteur, Université de Paris, CNRS, Inserm, University of Reims Champagne-Ardenne, Reims University Hospital and the Institut Pasteur de Lille focused their research on the variability of a single nucleotide (an adenine base rather than a guanine base) in the CHRNA5 gene, coding for the alpha5 subunit of the nAChR receptor, on chromosome 15.

This version of the gene occurs in the genomes of 37% of the European population. The scientists examined the effects of this variation on airway cells.

In the animal model carrying this version of the gene, the study showed the onset of emphysema destroying the pulmonary alveolar walls, a phenomenon observed in COPD patients.

We revealed the biological impact of a mutation in a gene linked to COPD,

said Valérian Dormoy, a lecturer and researcher at the Pulmonary Pathologies and Cellular Plasticity Inserm laboratory at the University of Reims Champagne-Ardenne and study joint last author.

Predisposing Factor

The scientists established a connection between the expression of this gene version and airway epithelium inflammation and remodeling.

Functional impairment was observed in progenitor airway basal cells located in the deep layer of the epithelium and responsible for epithelial renewal. The scientists observed this dysfunction particularly during scarring of the bronchial epithelium.

intracellular signaling in basal cells expressing α5SNP nAChR in response to epithelial stress

Scheme summarizing a mechanism of intracellular signaling in basal cells expressing α5SNP nAChR in response to epithelial stress. Credit: Routhier, J., Pons, S., Freidja, M.L. et al, CC-BY

The study findings were subsequently confirmed in humans. Histological analysis of cells from samples of nasal polyps from 123 non-smoking patients at Reims University Hospital also revealed a link between epithelial remodeling and this gene mutation.

This gene version appears to be a genetic predisposing factor for the disease independent of smoking. COPD onset then occurs subsequent to repeated lesions of airway tissue caused by other molecules including atmospheric pollutants,

added Philippe Birembaut, study joint last author.

The signaling pathways involved were identified through in vitro analysis of animal cells expressing the modified version of the nicotinic receptor. This could provide a pharmacological target for the development of a future treatment.

The work received support from the Agence Nationale de la Recherche, the Institut National du Cancer, the Ligue contre le Cancer Région Grand-Est, the Association de Recherche sur le, the CHU of Reims, the Prix de la Chancellerie Sorbonne, Legs Poix, Fondation pour la Recherche Médicale, the Lions Club of Soissons and Crépy-en-Valois, the Institut de Recherche en Santé Publique, Institut Pasteur, Inserm, CNRS, and the National Institutes of Health, among others.


  1. Routhier, J., Pons, S., Freidja, M.L. et al. An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions. Nat Commun 12, 6384 (2021). ↩︎

  2. Sakornsakolpat, P. et al. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nat. Genet. 51, 494–505 (2019). ↩︎


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