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Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Lookup NU author(s): Professor Dawn Teare, Dr Paul Brennan

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2020, The Author(s). Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10−8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10−12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21–1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01–1.35) and lung cancer in never smokers (OR = 1.56, 1.05–2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Publication metadata

Author(s): Kachuri L, Johansson M, Rashkin SR, Graff RE, Bosse Y, Manem V, Caporaso NE, Landi MT, Christiani DC, Vineis P, Liu G, Scelo G, Zaridze D, Shete SS, Albanes D, Aldrich MC, Tardon A, Rennert G, Chen C, Goodman GE, Doherty JA, Bickeboller H, Field JK, Davies MP, Teare MD, Kiemeney LA, Bojesen SE, Haugen A, Zienolddiny S, Lam S, Le Marchand L, Cheng I, Schabath MB, Duell EJ, Andrew AS, Manjer J, Lazarus P, Arnold S, McKay JD, Emami NC, Warkentin MT, Brhane Y, Obeidat M, Martin RM, Relton C, Davey Smith G, Haycock PC, Amos CI, Brennan P, Witte JS, Hung RJ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2020

Volume: 11

Online publication date: 07/01/2020

Acceptance date: 29/11/2019

Date deposited: 20/01/2020

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-019-13855-2

DOI: 10.1038/s41467-019-13855-2

PubMed id: 31911640


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Funding

Funder referenceFunder name
5R01 CA151989-01A1
C52724/A20138
C18281/A19169
FDN 167273
NIH U19 CA203654
P30 CA076292
R01 CA111703
NIH P50 CA119997
U01 CA6367307
UM1 CA167462
R01 CA201358
R25T CA112355
U01 CA167462
U01CA209414

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