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. GoodmanJennifer 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

Biostatistics

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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: 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 (US)
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

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Biostatistics Resource Group

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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

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

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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 × 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.",

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.}",

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AU - Kachuri, Linda

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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.

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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.

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

Abstract

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