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

Linda Kachuri; Mattias Johansson; Sara R. Rashkin; Rebecca E. Graff; Yohan Bossé; Venkata Manem; Neil E. Caporaso; Maria Teresa Landi; David C. Christiani; Paolo Vineis; Geoffrey Liu; Ghislaine Scelo; David Zaridze; Sanjay S. Shete; Demetrius Albanes; Melinda C. Aldrich; Adonina Tardón; Gad Rennert; Chu Chen; Gary E. Goodman; Jennifer A. Doherty; Heike Bickeböller; John K. Field; Michael P. Davies; M. Dawn Teare; Lambertus A. Kiemeney; Stig E. Bojesen; Aage Haugen; Shanbeh Zienolddiny; Stephen Lam; Loïc Le Marchand; Iona Cheng; Matthew B. Schabath; Eric J. Duell; Angeline S. Andrew; Jonas Manjer; Philip Lazarus; Susanne Arnold; James D. McKay; Nima C. Emami; Matthew T. Warkentin; Yonathan Brhane; Ma’en Obeidat; Richard M. Martin; Caroline Relton; George Davey Smith; Philip C. Haycock; Christopher I. Amos; Paul Brennan; John S. Witte; Rayjean J. Hung

doi:10.1038/s41467-019-13855-2

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

Linda Kachuri
, Mattias Johansson
, Sara R. Rashkin
, Rebecca E. Graff
, Yohan Bossé
, Venkata Manem
, Neil E. Caporaso
, Maria Teresa Landi
, David C. Christiani
, Paolo Vineis
, Geoffrey Liu
, Ghislaine Scelo
, David Zaridze
, Sanjay S. Shete
, Demetrius Albanes
, Melinda C. Aldrich
, Adonina Tardón
, Gad Rennert
, Chu Chen
, Gary E. Goodman

Jennifer A. Doherty, Heike Bickeböller, John K. Field, Michael P. Davies, M. Dawn Teare, Lambertus A. Kiemeney, Stig E. Bojesen, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Loïc Le Marchand, Iona Cheng, Matthew B. Schabath, Eric J. Duell, Angeline S. Andrew, Jonas Manjer, Philip Lazarus, Susanne Arnold, James D. McKay, Nima C. Emami, Matthew T. Warkentin, Yonathan Brhane, Ma’en Obeidat, Richard M. Martin, Caroline Relton, George Davey Smith, Philip C. Haycock, Christopher I. Amos, Paul Brennan, John S. Witte, Rayjean J. Hung

Pharmaceutical Sciences

University of California at San Francisco
University of Toronto
International Agency for Research on Cancer
Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval
National Institutes of Health
Harvard University
Imperial College London
University Health Network
Russian N.N. Blokhin Cancer Research Centre
University of Texas MD Anderson Cancer Center
Vanderbilt University
University of Oviedo
Clalit Health Services
Fred Hutchinson Cancer Research Center
University of Utah
University of Göttingen
University of Liverpool
Newcastle University
Radboud University Nijmegen
University of Copenhagen
National Institute of Occupational Health
Provincial Health Services Authority
University of Hawai'i at Mānoa
Moffitt Cancer Center
Bellvitge Biomedical Research Institute
Dartmouth College
Lund University
University of Kentucky
University of British Columbia
University of Bristol
University Hospitals Bristol NHS Foundation Trust and the University of Bristol
Baylor College of Medicine

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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: r_g = 0.098, p = 2.3 × 10⁻⁸) and the ratio of FEV₁ to forced vital capacity (FEV₁/FVC: r_g = 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 language	English
Article number	27
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13855-2
State	Published - Dec 1 2020

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Kachuri, L., Johansson, M., Rashkin, S. R., Graff, R. E., Bossé, Y., Manem, V., Caporaso, N. E., Landi, M. T., Christiani, D. C., Vineis, P., Liu, G., Scelo, G., Zaridze, D., Shete, S. S., Albanes, D., Aldrich, M. C., Tardón, 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), Article 27. https://doi.org/10.1038/s41467-019-13855-2

@article{78a025c3da644af8987fc1e8dddc9398,

title = "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 {\texttimes} 10−8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 {\texttimes} 10−12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95\% confidence intervals: 1.21{\textendash}1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01{\textendash}1.35) and lung cancer in never smokers (OR = 1.56, 1.05{\textendash}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.",

author = "Linda Kachuri and Mattias Johansson and Rashkin, \{Sara R.\} and Graff, \{Rebecca E.\} and Yohan Boss{\'e} and Venkata Manem and Caporaso, \{Neil E.\} and Landi, \{Maria Teresa\} and Christiani, \{David C.\} and Paolo Vineis and Geoffrey Liu and Ghislaine Scelo and David Zaridze and Shete, \{Sanjay S.\} and Demetrius Albanes and Aldrich, \{Melinda C.\} and Adonina Tard{\'o}n and Gad Rennert and Chu Chen and Goodman, \{Gary E.\} and Doherty, \{Jennifer A.\} and Heike Bickeb{\"o}ller and Field, \{John K.\} and Davies, \{Michael P.\} and \{Dawn Teare\}, M. and Kiemeney, \{Lambertus A.\} and Bojesen, \{Stig E.\} and Aage Haugen and Shanbeh Zienolddiny and Stephen Lam and \{Le Marchand\}, Lo{\"i}c and Iona Cheng and Schabath, \{Matthew B.\} and Duell, \{Eric J.\} and Andrew, \{Angeline S.\} and Jonas Manjer and Philip Lazarus and Susanne Arnold and McKay, \{James D.\} and Emami, \{Nima C.\} and Warkentin, \{Matthew T.\} and Yonathan Brhane and Ma{\textquoteright}en Obeidat and Martin, \{Richard M.\} and Caroline Relton and \{Davey Smith\}, George and Haycock, \{Philip C.\} and Amos, \{Christopher I.\} and Paul Brennan and Witte, \{John S.\} and Hung, \{Rayjean J.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13855-2",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Kachuri, L, Johansson, M, Rashkin, SR, Graff, RE, Bossé, Y, Manem, V, Caporaso, NE, Landi, MT, Christiani, DC, Vineis, P, Liu, G, Scelo, G, Zaridze, D, Shete, SS, Albanes, D, Aldrich, MC, Tardón, A, Rennert, G, Chen, C, Goodman, GE, Doherty, JA, Bickeböller, H, Field, JK, Davies, MP, Dawn Teare, M, 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 2020, 'Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility', Nature Communications, vol. 11, no. 1, 27. https://doi.org/10.1038/s41467-019-13855-2

TY - JOUR

T1 - Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

AU - Kachuri, Linda

AU - Johansson, Mattias

AU - Rashkin, Sara R.

AU - Graff, Rebecca E.

AU - Bossé, Yohan

AU - Manem, Venkata

AU - Caporaso, Neil E.

AU - Landi, Maria Teresa

AU - Christiani, David C.

AU - Vineis, Paolo

AU - Liu, Geoffrey

AU - Scelo, Ghislaine

AU - Zaridze, David

AU - Shete, Sanjay S.

AU - Albanes, Demetrius

AU - Aldrich, Melinda C.

AU - Tardón, Adonina

AU - Rennert, Gad

AU - Chen, Chu

AU - Goodman, Gary E.

AU - Doherty, Jennifer A.

AU - Bickeböller, Heike

AU - Field, John K.

AU - Davies, Michael P.

AU - Dawn Teare, M.

AU - Kiemeney, Lambertus A.

AU - Bojesen, Stig E.

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Lam, Stephen

AU - Le Marchand, Loïc

AU - Cheng, Iona

AU - Schabath, Matthew B.

AU - Duell, Eric J.

AU - Andrew, Angeline S.

AU - Manjer, Jonas

AU - Lazarus, Philip

AU - Arnold, Susanne

AU - McKay, James D.

AU - Emami, Nima C.

AU - Warkentin, Matthew T.

AU - Brhane, Yonathan

AU - Obeidat, Ma’en

AU - Martin, Richard M.

AU - Relton, Caroline

AU - Davey Smith, George

AU - Haycock, Philip C.

AU - Amos, Christopher I.

AU - Brennan, Paul

AU - Witte, John S.

AU - Hung, Rayjean J.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85077517966

U2 - 10.1038/s41467-019-13855-2

DO - 10.1038/s41467-019-13855-2

M3 - Article

C2 - 31911640

AN - SCOPUS:85077517966

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 27

ER -

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

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