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PLoS One. 2017 Jun 8;12(6):e0177875. doi: 10.1371/journal.pone.0177875. eCollection 2017.

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

Author information

1
Section of Genetics, International Agency for Research on Cancer (IARC), Lyon, France.
2
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
3
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.
4
Metabolic Epidemiology Branch, DCEG, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
5
Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
6
Norris Cotton Cancer Center, Lebanon, New Hampshire, United States of America.
7
University of Kentucky Markey Cancer Center, Lexington, Kentucky, United States of America.
8
University Medical Center Göettingen, Göttingen, Germany.
9
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Laboratory Medicine Region Skåne, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
11
Helmholtz Zentrum München, Munich, Germany.
12
Genetic Epidemiology Branch, DCEG, National Cancer Institute, NIH, Rockville, Maryland, United States of America.
13
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
14
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.
15
Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, Kentucky, United States of America.
16
Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, United States of America.
17
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.
18
Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool, United Kingdom.
19
Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
20
Department of Medical Biosciences, Umeå University, Umeå, Sweden.
21
National Institute of Occupational Health, Oslo, Norway.
22
Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
23
Radboud University Medical Center, Nijmegen, The Nederlands.
24
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
25
British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
26
Washington State University College of Pharmacy, Spokane, Washington, United States of America.
27
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
28
Ontario Cancer Institute, Princess Margaret Cancer Center, Toronto, Ontario, Canada.
29
Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
30
Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
31
Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
32
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.
33
University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
34
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
35
Russian N.N. Blokhin Cancer Research Centre, Moscow, The Russian Federation.
36
Department of Thoracic Surgery, Clinical Center of Serbia, Belgrade, Serbia.
37
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.
38
Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland.
39
Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
40
Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic.
41
National Institute of Public Health, Bucharest, Romania.
42
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
43
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.
44
Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo and CIBERESP, Oviedo, Spain.
45
University of Sheffield, Sheffield, United Kingdom.
46
Princess Margaret Cancer Center, Toronto, Canada.
47
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
48
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.
49
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada.
50
Department of Biomedical Data Science, Geisel School of medicine, Dartmouth College, Lebanon, New Hampshire, United States of America.

Abstract

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.

PMID:
28594918
PMCID:
PMC5464539
DOI:
10.1371/journal.pone.0177875
[Indexed for MEDLINE]
Free PMC Article

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