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

Author

Listed:
  • 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
    University of M’sila)

  • Véronique Dalstein

    (Université de Reims Champagne-Ardenne, Inserm
    CHU of Reims)

  • 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
    CHU of Reims)

  • 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
    CHU of Reims)

  • Valérian Dormoy

    (Université de Reims Champagne-Ardenne, Inserm)

  • Uwe Maskos

    (Institut Pasteur, Université de Paris, Integrative Neurobiology of Cholinergic Systems)

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.

Suggested Citation

  • Julie Routhier & Stéphanie Pons & Mohamed Lamine Freidja & Véronique Dalstein & Jérôme Cutrona & Antoine Jonquet & Nathalie Lalun & Jean-Claude Mérol & Mark Lathrop & Jerry A. Stitzel & Gwenola Kervoa, 2021. "An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26637-6
    DOI: 10.1038/s41467-021-26637-6
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    References listed on IDEAS

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    1. Masahiro Yoshida & Shunsuke Minagawa & Jun Araya & Taro Sakamoto & Hiromichi Hara & Kazuya Tsubouchi & Yusuke Hosaka & Akihiro Ichikawa & Nayuta Saito & Tsukasa Kadota & Nahoko Sato & Yusuke Kurita & , 2019. "Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
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    3. Kai Cui & Xiaoyan Ge & Honglin Ma, 2014. "Four SNPs in the CHRNA3/5 Alpha-Neuronal Nicotinic Acetylcholine Receptor Subunit Locus Are Associated with COPD Risk Based on Meta-Analyses," PLOS ONE, Public Library of Science, vol. 9(7), pages 1-8, July.
    4. Rayjean J. Hung & James D. McKay & Valerie Gaborieau & Paolo Boffetta & Mia Hashibe & David Zaridze & Anush Mukeria & Neonilia Szeszenia-Dabrowska & Jolanta Lissowska & Peter Rudnai & Eleonora Fabiano, 2008. "A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25," Nature, Nature, vol. 452(7187), pages 633-637, April.
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