Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study

Research output: Contribution to journalArticle


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.


  • Robert Carreras-Torres
  • Mattias Johansson
  • Philip C Haycock
  • Kaitlin H Wade
  • Caroline L Relton
  • Richard M Martin
  • George Davey-Smith
  • Demetrius Albanes
  • Melinda C Aldrich
  • Angeline S Andrew
  • Susanne M Arnold
  • Heike Bickeböller
  • Stig E. Bojesen
  • Irene Brüske
  • Neil E Caporaso
  • Chu Chen
  • David C. Christiani
  • W Jay Christian
  • Jennifer A Doherty
  • Eric J. Duell
  • John K. Field
  • Michael P A Davies
  • Michael W Marcus
  • Gary E Goodman
  • Kjell Grankvist
  • Aage Haugen
  • Yun-Chul Hong
  • Lambertus A. Kiemeney
  • Erik H F M van der Heijden
  • Peter Kraft
  • Mikael B Johansson
  • Stephen Lam
  • Maria Teresa Landi
  • Philip Lazarus
  • Loïc Le Marchand
  • Geoffrey Liu
  • Sungshim L Park
  • Gad Rennert
  • Angela Risch
  • Eric B Haura
  • Ghislaine Scelo
  • David Zaridze
  • Anush Mukeriya
  • Milan Savić
  • Jolanta Lissowska
  • Beata Swiatkowska
  • Vladimir Janout
  • Ivana Holcatova
  • Dana Mates
  • Matthew B Schabath
  • Hongbing Shen
  • Adonina Tardon
  • M Dawn Teare
  • Penella Woll
  • Ming-Sound Tsao
  • Xifeng Wu
  • Jian-Min Yuan
  • Rayjean J. Hung
  • Christopher I Amos
  • James McKay
  • Paul Brennan
External organisations
  • University of Bristol
  • University of Kentucky
  • University of Göttingen
  • University of Copenhagen
  • Helmholtz Zentrum München
  • Dartmouth College
  • Catalan Institute of Oncology
  • University of Liverpool
  • Fred Hutchinson Cancer Research Center
  • Umeå University
  • National Institute of Occupational Health, Norway
  • Seoul National University
  • Radboud University Medical Center
  • Harvard T.H. Chan School of Public Health
  • British Columbia Cancer Agency
  • Washington State University College of Pharmacy
  • University of Hawaii Cancer Center
  • Princess Margaret Hospital University of Toronto
  • University of Southern California
  • Technion - Israel Institute of Technology
  • University of Salzburg
  • H. Lee Moffitt Cancer Center & Research Institute
  • N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences
  • Clinical Center of Serbia
  • The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
  • University of Ostrava
  • Charles University in Prague
  • National Institute of Public Health, Romania
  • Nanjing Medical University
  • University of Oviedo
  • University of Sheffield
  • University of Texas
  • University of Pittsburgh Cancer Institute
  • Mount Sinai Hospital of University of Toronto
  • Regional Laboratories Region Skåne
  • Skåne University Hospital
  • International Agency for Research on Cancer, World Health Organization
  • National Cancer Institute, USA
  • Vanderbilt University
  • Norris Cotton Cancer Center
  • National Cancer Institute, NCI
  • Harvard Medical School
  • Nofer Institute of Occupational Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Article numbere0177875
JournalPLoS ONE
Issue number6
Publication statusPublished - 2017
Publication categoryResearch