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.

British Columbia Cancer Agency Vancouver British Columbia Canada

Clalit National Cancer Control Center and Department of Community Medicine and Epidemiology Carmel Medical Center and B Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

Department of Biomedical Data Science Geisel School of medicine Dartmouth College Lebanon New Hampshire United States of America

Department of Cancer Epidemiology and Prevention Maria Sklodowska Curie Institute Oncology Center Warsaw Poland

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa Florida United States of America

Department of Clinical Sciences Malmö Lund University Lund Sweden

Department of Epidemiology and Biostatistics Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Cancer Personalized Medicine School of Public Health Nanjing Medical University Nanjing China

Department of Epidemiology and Public Health Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Epidemiology College of Public Health University of Kentucky Lexington Kentucky United States of America

Department of Epidemiology Geisel School of Medicine Dartmouth College Lebanon New Hampshire United States of America

Department of Epidemiology Harvard T H Chan School of Public Health Boston Massachusetts United States of America

Department of Internal Medicine Skåne University Hospital Malmö Sweden

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Preventive Medicine Seoul National University College of Medicine Seoul Korea

Department of Thoracic Oncology H Lee Moffitt Cancer Center and Research Institute Tampa Florida United States of America

Department of Thoracic Surgery Clinical Center of Serbia Belgrade Serbia

Department of Thoracic Surgery Division of Epidemiology Vanderbilt University Medical Center Nashville Tennessee United States of America

Departments of Environmental Health and Epidemiology Harvard T H Chan School of Public Health and Department of Medicine Massachusetts General Hospital Harvard Medical School Boston Massachusetts United States of America

Division of Cancer Control and Population Science University of Pittsburgh Cancer Institute; and Department of Epidemiology University of Pittsburgh Graduate School of Public Health Pittsburgh Pennsylvania United States of America

Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii United States of America

Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Fred Hutchinson Cancer Research Center Seattle Washington United States of America

Genetic Epidemiology Branch DCEG National Cancer Institute NIH Rockville Maryland United States of America

Helmholtz Zentrum München Munich Germany

Institute of Public Health and Preventive Medicine Charles University 2nd Faculty of Medicine Prague Czech Republic

Instituto Universitario de Oncología del Principado de Asturias University of Oviedo and CIBERESP Oviedo Spain

Laboratory Medicine Region Skåne Department of Clinical Sciences Lund Lund University Lund Sweden

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Canada

Metabolic Epidemiology Branch DCEG National Cancer Institute NIH Rockville Maryland United States of America

MRC Integrative Epidemiology Unit School of Social and Community Medicine University of Bristol Bristol United Kingdom

National Institute for Health Research Biomedical Research Unit in Nutrition Diet and Lifestyle at University Hospitals Bristol NHS Foundation Trust and the University of Bristol Bristol United Kingdom

National Institute of Occupational Health Oslo Norway

National Institute of Public Health Bucharest Romania

Nofer Institute of Occupational Medicine Department of Environmental Epidemiology Lodz Poland

Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles California United States of America

Norris Cotton Cancer Center Lebanon New Hampshire United States of America

Ontario Cancer Institute Princess Margaret Cancer Center Toronto Ontario Canada

Princess Margaret Cancer Center Toronto Canada

Program in Epidemiology Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington United States of America

Radboud University Medical Center Nijmegen The Nederlands

Roy Castle Lung Cancer Research Programme Department of Molecular and Clinical Cancer Medicine Institute of Translational Medicine The University of Liverpool Liverpool United Kingdom

Russian N N Blokhin Cancer Research Centre Moscow The Russian Federation

Section of Genetics International Agency for Research on Cancer Lyon France

The University of Texas MD Anderson Cancer Center Houston Texas United States of America

Unit of Nutrition and Cancer Cancer Epidemiology Research Program Catalan Institute of Oncology Barcelona Spain

University Medical Center Göettingen Göttingen Germany

University of Kentucky Markey Cancer Center Lexington Kentucky United States of America

University of Salzburg and Cancer Cluster Salzburg Salzburg Austria

University of Sheffield Sheffield United Kingdom

Washington State University College of Pharmacy Spokane Washington United States of America

See more in PubMed

Torre LA, Bray F, Siegel RL, Ferlay J. Global Cancer Statistics, 2012. CA Cancer J Clin. 2015;65: 87–108. 10.3322/caac.21262 PubMed DOI

International Agency for Research on Cancer. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 114. [Internet]. 2015. http://monographs.iarc.fr/ENG/Classification/index.php

Bhaskaran K, Douglas I, Forbes H, dos-Santos-Silva I, Leon D a., Smeeth L. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet. 2014; 755–765. 10.1016/S0140-6736(14)60892-8 PubMed DOI PMC

Kabat GC, Kim M, Hunt JR, Chlebowski RT, Rohan TE. Body mass index and waist circumference in relation to lung cancer risk in the women’s health initiative. Am J Epidemiol. 2008;168: 158–169. 10.1093/aje/kwn109 PubMed DOI PMC

Lam TK, Moore SC, Brinton L a., Smith L, Hollenbeck AR, Gierach GL, et al. Anthropometric Measures and Physical Activity and the Risk of Lung Cancer in Never-Smokers: A Prospective Cohort Study. PLoS One. 2013;8 10.1371/journal.pone.0070672 PubMed DOI PMC

Smith L, Brinton L a., Spitz MR, Lam TK, Park Y, Hollenbeck AR, et al. Body mass index and risk of lung cancer among never, former, and current smokers. J Natl Cancer Inst. 2012;104: 778–789. 10.1093/jnci/djs179 PubMed DOI PMC

Yang Y, Dong J, Sun K, Zhao L, Zhao F, Wang L, et al. Obesity and incidence of lung cancer: A meta-analysis. Int J Cancer. 2013;132: 1162–1169. 10.1002/ijc.27719 PubMed DOI

Kucharska-newton AM, Rosamond WD, Schroeder JC, Marie A, Coresh J, Folsom AR. HDL-cholesterol and the incidence of lung cancer in the Atherosclerosis Risk in Communities (ARIC) study. Lung Cancer. 2009;61: 292–300. PubMed PMC

Puchades-Carrasco L, Jantus-Lewintre E, Pérez-Rambla C, Camps C, Pineda-Lucena A. Serum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer. Oncotarget. 2016;7: 12904–16. 10.18632/oncotarget.7354 PubMed DOI PMC

Melkonian SC, Daniel CR, Ye Y, Pierzynski JA, Roth JA, Wu X. Glycemic Index, Glycemic Load, and Lung Cancer Risk in Non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev. 2016;25: 532–540. 10.1158/1055-9965.EPI-15-0765 PubMed DOI PMC

Ho GYF, Zheng SL, Cushman M, Perez-soler R, Kim M, Xue X, et al. Associations of Insulin and IGFBP-3 with Lung Cancer Susceptibility in Current Smokers. J Natl Cancer Inst. 2016;108: djw012. 10.1093/jnci/djw012 PubMed DOI PMC

Freathy RM, Kazeem GR, Morris RW, Johnson PCD, Paternoster L, Ebrahim S, et al. Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index. Int J Epidemiol. 2011;40: 1617–1628. 10.1093/ije/dyr077 PubMed DOI PMC

Taylor AE, Morris RW, Fluharty ME, Bjorngaard JH, Åsvold BO, Gabrielsen ME, et al. Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers. PLoS Genet. 2014;10: e1004799 10.1371/journal.pgen.1004799 PubMed DOI PMC

Winslow UC, Rode L, Nordestgaard BG. High tobacco consumption lowers body weight: a Mendelian randomization study of the Copenhagen General Population Study. Int J Epidemiol. 2015;44: 540–550. 10.1093/ije/dyu276 PubMed DOI

Davey Smith G, Ebrahim S. Mendelian randomization ‘: can genetic epidemiology contribute to understanding environmental determinants of disease ? Int J Epidemiol. 2003; 1–22. 10.1093/ije/dyg070 PubMed DOI

Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23: 1–10. PubMed PMC

Burgess S, Butterworth AS, Thompson JR. Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors. J Clin Epidemiol. Elsevier; 2016;69: 208–216. 10.1016/j.jclinepi.2015.08.001 PubMed DOI PMC

Carreras-Torres R, Haycock PC, Relton CL, Martin RM, Smith GD, Kraft P, et al. The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study. Sci Rep. 2016;6: 31121 10.1038/srep31121 PubMed DOI PMC

Gao C, Patel CJ, Michailidou K, Peters U, Gong J, Schildkraut J, et al. Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer. Int J Epidemiol. 2016; dyw129. 10.1093/ije/dyw129 PubMed DOI PMC

Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37: 658–65. 10.1002/gepi.21758 PubMed DOI PMC

Burgess S, Scott R a, Timpson NJ, Davey-smith G, Thompson SG. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. Springer Netherlands; 2014; 1–39. 10.1007/s10654-015-0011-z PubMed DOI PMC

Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526: 75–81. 10.1038/nature15394 PubMed DOI PMC

Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518: 197–206. 10.1038/nature14177 PubMed DOI PMC

Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira Teresa, Locke AE, et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518: 187–196. 10.1038/nature14132 PubMed DOI PMC

Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45: 1274–1283. 10.1038/ng.2797 PubMed DOI PMC

Helgadottir A, Gretarsdottir S, Thorleifsson G, Hjartarson E, Sigurdsson A, Magnusdottir A, et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet. 2016;48: 634–639. 10.1038/ng.3561 PubMed DOI PMC

Scott RA, Lagou V, Welch RP, Wheeler E, May E. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet. 2012;44: 991–1005. 10.1038/ng.2385 PubMed DOI PMC

McKay JD, Hun RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet. 2017; PubMed PMC

Timofeeva MN, Hung RJ, Rafnar T, Christiani DC, Field JK, Bickeböller H, et al. Influence of common genetic variation on lung cancer risk: Meta-analysis of 14 900 cases and 29 485 controls. Hum Mol Genet. 2012;21: 4980–4995. 10.1093/hmg/dds334 PubMed DOI PMC

Burgess S. Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome. Int J Epidemiol. 2014;43: 922–929. 10.1093/ije/dyu005 PubMed DOI PMC

Bowden J, Smith GD, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40: 304–14. 10.1002/gepi.21965 PubMed DOI PMC

Bowden J, Del Greco M F, Minelli C, Davey Smith G, Sheehan NA, Thompson JR. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int J Epidemiol. 2016; 1–14. 10.1093/ije/dyw220 PubMed DOI PMC

Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015; 512–525. 10.1093/ije/dyv080 PubMed DOI PMC

Hemani G, Zheng J, Wade KH, Elsworth B, Langdon R, Burgess S, et al. MR-Base: a platform for systematic causal inference across the phenome using billions of genetic associations. bioRxiv. 2016; 10.1101/078972 DOI

Furberg H, Kim Y, Dackor J, Boerwinkle E, Franceschini N, Ardissino D, et al. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet. 2010;42: 441–447. 10.1038/ng.571 PubMed DOI PMC

Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D. Metabolic Syndrome and Risk of Cancer. A systematic review and meta-analysis. Diabetes Care. 2012;35: 2402–2411. 10.2337/dc12-0336 PubMed DOI PMC

Radisauskas R, Kuzmickien I, Milinaviciene E, Everatt R. Hypertension, serum lipids and cancer risk: A review of epidemiological evidence. Medicina (B Aires). 2016;52: 89–98. 10.1016/j.medici.2016.03.002 PubMed DOI

Nead KT, Sharp SJ, Thompson DJ, Painter JN, Savage DB, Semple RK, et al. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis. J Natl Cancer Inst. 2015;107: 1–7. 10.1093/jnci/djv178 PubMed DOI PMC

Carreras-Torres R, Johansson M, Gaborieau V, Haycock PC, Wade KH, Relton CL, et al. The role of obesity, type 2 diabetes, and metabolic factors in pancreatic cancer: A Mendelian randomization study. J Natl Cancer Inst. 2017;109: djx012. PubMed PMC

Braun S, Bitton-worms K, Leroith D. The Link between the Metabolic Syndrome and Cancer. Int J Biol Sci. 2011;7: 1003–1015. PubMed PMC

Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106: 473–481. 10.1172/JCI10842 PubMed DOI PMC

Renehan AG, Zwahlen M, Egger M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer. 2015;15: 484–498. 10.1038/nrc3967 PubMed DOI

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers