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

Linda Kachuri, Mattias Johansson, Sara Rashkin, Rebecca Graff, Yohan Bossé, Venkata Manem, Neil E Caporaso, Maria Teresa Landi, David C Christiani, Paolo Vineis, Geoffrey Liu, Ghislaine Scelo, David Zaridze, Sanjay Shete, Demetrius Albanes, Melinda Aldrich, Adonina Tardon, Gad Rennert, Chu Chen, Gary E GoodmanJennifer A Doherty, Heike Bickeböller, John K Field, Michael Davis, M Dawn Teare, Lambertus A L M Kiemeney, Stig E Bojesen, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Loic Le Marchand, Iona Cheng, Matthew B. Schabath, Eric J Duell, Angeline S. Andrew, Jonas Manjer, Philip Lazarus, Susanne M. Arnold, James D McKay, Nima Emami, Matthew Warkentin, Yonathan Brhane, Ma'en Obeidat, Richard M Martin, Caroline L Relton, George Davey Smith, Philip C Haycock, Christopher I. Amos, Paul Brennan, John S Witte, Rayjean J. Hung

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Abstract

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.

Original languageEnglish
Article number27 (2020)
Number of pages14
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 7 Jan 2020

Structured keywords

  • ICEP
  • Bristol Population Health Science Institute

Keywords

  • Cancer epidemiology
  • Genetics research

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    Kachuri, L., Johansson, M., Rashkin, S., Graff, R., Bossé, Y., Manem, V., Caporaso, N. E., Landi, M. T., Christiani, D. C., Vineis, P., Liu, G., Scelo, G., Zaridze, D., Shete, S., Albanes, D., Aldrich, M., Tardon, A., Rennert, G., Chen, C., ... Hung, R. J. (2020). Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility. Nature Communications, 11(1), [27 (2020)]. https://doi.org/10.1038/s41467-019-13855-2, https://doi.org/10.1038/s41467-019-13855-2