An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions

Julie Routhier, Stéphanie Pons, Mohamed Lamine Freidja, Véronique Dalstein, Jérôme Cutrona, Antoine Jonquet, Nathalie Lalun, Jean-Claude Mérol, Mark Lathrop, Jerry A. Stitzel, Gwenola Kervoaze, Muriel Pichavant, Philippe Gosset, Jean-Marie Tournier, Philippe Birembaut, Valérian Dormoy () and Uwe Maskos ()
Additional contact information
Julie Routhier: Université de Reims Champagne-Ardenne, Inserm
Stéphanie Pons: Institut Pasteur, Université de Paris, Integrative Neurobiology of Cholinergic Systems
Mohamed Lamine Freidja: Université de Reims Champagne-Ardenne, Inserm
Véronique Dalstein: Université de Reims Champagne-Ardenne, Inserm
Jérôme Cutrona: Université de Reims Champagne-Ardenne, Inserm
Antoine Jonquet: Université de Reims Champagne-Ardenne, Inserm
Nathalie Lalun: Université de Reims Champagne-Ardenne, Inserm
Jean-Claude Mérol: Université de Reims Champagne-Ardenne, Inserm
Mark Lathrop: McGill University Genome Center
Jerry A. Stitzel: Institute for Behavioral Genetics, University of Colorado
Gwenola Kervoaze: University of Lille, CNRS UMR9017, Inserm U1019, CHU Lille, Institut Pasteur de Lille, CIIL - Center for Infection and Immunity of Lille
Muriel Pichavant: University of Lille, CNRS UMR9017, Inserm U1019, CHU Lille, Institut Pasteur de Lille, CIIL - Center for Infection and Immunity of Lille
Philippe Gosset: University of Lille, CNRS UMR9017, Inserm U1019, CHU Lille, Institut Pasteur de Lille, CIIL - Center for Infection and Immunity of Lille
Jean-Marie Tournier: Université de Reims Champagne-Ardenne, Inserm
Philippe Birembaut: Université de Reims Champagne-Ardenne, Inserm
Valérian Dormoy: Université de Reims Champagne-Ardenne, Inserm
Uwe Maskos: Institut Pasteur, Université de Paris, Integrative Neurobiology of Cholinergic Systems

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26637-6

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DOI: 10.1038/s41467-021-26637-6

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