Dataset Information

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

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.

SUBMITTER: Kachuri L

PROVIDER: S-EPMC6946810 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kachuri Linda L Johansson Mattias M Rashkin Sara R SR Graff Rebecca E RE Bossé Yohan Y Manem Venkata V Caporaso Neil E NE Landi Maria Teresa MT Christiani David C DC Vineis Paolo P Liu Geoffrey G Scelo Ghislaine G Zaridze David D Shete Sanjay S SS Albanes Demetrius D Aldrich Melinda C MC Tardón Adonina A Rennert Gad G Chen Chu C Goodman Gary E GE Doherty Jennifer A JA Bickeböller Heike H Field John K JK Davies Michael P MP Dawn Teare M M Kiemeney Lambertus A LA Bojesen Stig E SE Haugen Aage A Zienolddiny Shanbeh S Lam Stephen S Le Marchand Loïc L Cheng Iona I Schabath Matthew B MB Duell Eric J EJ Andrew Angeline S AS Manjer Jonas J Lazarus Philip P Arnold Susanne S McKay James D JD Emami Nima C NC Warkentin Matthew T MT Brhane Yonathan Y Obeidat Ma'en M Martin Richard M RM Relton Caroline C Davey Smith George G Haycock Philip C PC Amos Christopher I CI Brennan Paul P Witte John S JS Hung Rayjean J RJ

Nature communications 20200107 1

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 forc ...[more]

PMID: 31911640

Similar Datasets

Project description:Pulmonary tuberculosis (TB) is caused by Mycobacterium tuberculosis in susceptible humans. Here, we infected Diversity Outbred (DO) mice with ?100 bacilli by aerosol to model responses in a highly heterogeneous population. Following infection, 'supersusceptible', 'susceptible' and 'resistant' phenotypes emerged. TB disease (reduced survival, weight loss, high bacterial load) correlated strongly with neutrophils, neutrophil chemokines, tumor necrosis factor (TNF) and cell death. By contrast, immune cytokines were weak correlates of disease. We next applied statistical and machine learning approaches to our dataset of cytokines and chemokines from lungs and blood. Six molecules from the lung: TNF, CXCL1, CXCL2, CXCL5, interferon-? (IFN-?), interleukin 12 (IL-12); and two molecules from blood - IL-2 and TNF - were identified as being important by applying both statistical and machine learning methods. Using molecular features to generate tree classifiers, CXCL1, CXCL2 and CXCL5 distinguished four classes (supersusceptible, susceptible, resistant and non-infected) from each other with approximately 77% accuracy using completely independent experimental data. By contrast, models based on other molecules were less accurate. Low to no IFN-?, IL-12, IL-2 and IL-10 successfully discriminated non-infected mice from infected mice but failed to discriminate disease status amongst supersusceptible, susceptible and resistant M.-tuberculosis-infected DO mice. Additional analyses identified CXCL1 as a promising peripheral biomarker of disease and of CXCL1 production in the lungs. From these results, we conclude that: (1) DO mice respond variably to M. tuberculosis infection and will be useful to identify pathways involving necrosis and neutrophils; (2) data from DO mice is suited for machine learning methods to build, validate and test models with independent data based solely on molecular biomarkers; (3) low levels of immunological cytokines best indicate a lack of exposure to M. tuberculosis but cannot distinguish infection from disease.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets