Robert Carreras-Torres, International Agency for Research on Cancer (IARC)Follow
Mattias Johansson, International Agency for Research on Cancer (IARC)
Philip C. Haycock, University of Bristol
Kaitlin H. Wade, University of Bristol
Caroline L. Relton, University of Bristol
Richard M. Martin, University of Bristol
George Davey Smith, University of Bristol
Demetrius Albanes, National Cancer Institute, NIH, Rockville, Maryland
Melinda C. Aldrich, Vanderbilt UniversityFollow
Angeline Andrew, Norris Cotton Cancer CenterFollow
Susanne M. Arnold, University of Kentucky Markey Cancer Center
Heike Bickeböller, University Medical Center GöettingenFollow
Stig E. Bojesen, University of CopenhagenFollow
Hans Brunnstrom, Lund University
Jonas Manjer, Lund University
Irene Brüske, Helmholtz Zentrum München
Neil E. Caporaso, National Cancer Institute, NIH, Rockville, Maryland
Chu Chen, Fred Hutchinson Cancer Research CenterFollow
David C. Christiani, Harvard Medical School
W. Jay Christian, University of Kentucky
Jennifer Doherty, Dartmouth CollegeFollow
Eric J. Duell, Catalan Institute of Oncology (ICO-IDIBELL)
John K. Field, The University of LiverpoolFollow
Michael P.A Davies, The University of LiverpoolFollow
Michael W. Marcus, The University of Liverpool
Gary E. Goodman, Fred Hutchinson Cancer Research CenterFollow
Kjell Grankvist, Umeå University
Aage Haugen, National Institute of Occupational Health, Oslo, Norway
Yun-Chul Hong, Seoul National University College of Medicine
Lambertus A. Kiemeney, Radboud University Medical Center
Erik H.F.M van der Heijden, Radboud University Medical Center
Peter Kraft, Harvard T.H. Chan School of Public Health
Mikael B. Johansson, Umeå University
Stephen Lam, British Columbia Cancer Agency
Maria Teresa Landi, National Cancer Institute, NIH, Rockville, Maryland
Philip Lazarus, Washington State University
Loic Le Marchand, University of Hawaii, Honolulu
Geoffrey Liu, Princess Margaret Cancer Center, Toronto, Ontario
Olle Melander, Lund University
Sungshim L. Park, University of Southern California, Los Angeles
Gad Rennert, Technion-Israel Institute of Technology
Angela Risch, University of Salzburg
Eric B. Haura, H. Lee Moffitt Cancer Center and Research Institute
Ghislaine Scelo, International Agency for Research on Cancer (IARC), Lyon, France
David Zaridze, Russian N.N. Blokhin Cancer Research Centre
Anush Mukeriya, Russian N.N. Blokhin Cancer Research Centre
Milan Savić, Clinical Center of Serbia
Jolanta Lissowska, Maria Sklodowska-Curie Institute
Beata Swiatkowska, Nofer Institute of Occupational Medicine
Vladmir Janout, University of Ostrava
Ivana Holcatova, Charles University
Dana Mates, National Institute of Public Health, Bucharest, Romania
Matthew B. Schabath, H. Lee Moffitt Cancer Center and Research Institute
Hongbing Shen, Nanjing Medical University
Adonina Tardon, University of Oviedo and CIBERESP
M. Dawn Teare, University of Sheffield
Penella Woll, University of Sheffield
Ming-Sound Tsao, Princess Margaret Cancer Center
Xifeng Wu, The University of Texas MD Anderson Cancer Center
Jian-Min Yuan, University of Pittsburgh Cancer Institute
Rayjean J. Hung, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Christopher I. Amos, Dartmouth CollegeFollow
James McKay, International Agency for Research on Cancer (IARC)
Paul Brennan, International Agency for Research on Cancer (IARC)Follow

Document Type


Publication Date


Publication Title

PloS One


Geisel School of Medicine


Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.



Original Citation

Carreras-Torres R, Johansson M, Haycock PC, Wade KH, Relton CL, Martin RM, Davey Smith G, Albanes D, Aldrich MC, Andrew A, Arnold SM, Bickeböller H, Bojesen SE, Brunnström H, Manjer J, Brüske I, Caporaso NE, Chen C, Christiani DC, Christian WJ, Doherty JA, Duell EJ, Field JK, Davies MPA, Marcus MW, Goodman GE, Grankvist K, Haugen A, Hong YC, Kiemeney LA, van der Heijden EHFM, Kraft P, Johansson MB, Lam S, Landi MT, Lazarus P, Le Marchand L, Liu G, Melander O, Park SL, Rennert G, Risch A, Haura EB, Scelo G, Zaridze D, Mukeriya A, Savić M, Lissowska J, Swiatkowska B, Janout V, Holcatova I, Mates D, Schabath MB, Shen H, Tardon A, Teare MD, Woll P, Tsao MS, Wu X, Yuan JM, Hung RJ, Amos CI, McKay J, Brennan P. Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study. PLoS One. 2017 Jun 8;12(6):e0177875. doi: 10.1371/journal.pone.0177875. PMID: 28594918; PMCID: PMC5464539.