Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization
Open accessAbstract
At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two‐sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome‐wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small‐cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24‐2.06, P = 2.70 × 10 −4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR MVMR = 1.28, 95% CI = 1.06‐1.55, P MVMR = .011), and an inverse effect on lung adenocarcinoma (OR MVMR = 0.86, 95% CI = 0.77‐0.96, P MVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR UVMR = 1.19, 95% CI = 1.01‐1.40, P UVMR = .036), but this effect disappeared after adjustment of smoking (OR MVMR = 1.02, 95% CI = 0.90‐1.16, P MVMR = .746). These results highlight the histology‐specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
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The situation with MR is moving towards the one seen in the meta-analysis literature, with the mass production of redundant, misleading, and conflicted publications.
“The situation with MR is now moving towards the one seen in the meta-analysis literature, with the mass production of redundant, misleading, and conflicted publications.183”
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- Authors
- Zhou, W., Liu, G., Hung, R. J., Haycock, P. C., Aldrich, M. C., Andrew, A. S., Arnold, S. M., Bickeböller, H., Bojesen, S. E., Brennan, P., Brunnström, H., Melander, O., Caporaso, N. E., Landi, M. T., Chen, C., Goodman, G. E., Christiani, D. C., Cox, A., Field, J. K., Johansson, M., Kiemeney, L. A., Lam, S., Lazarus, P., Le Marchand, L., Rennert, G., Risch, A., Schabath, M. B., Shete, S. S., Tardón, A., Zienolddiny, S., Shen, H., & Amos, C. I.
- Affiliations
- Baylor College of Medicine (US)
- University Health Network (CA)
- University of Toronto (CA)
- University of Bristol (GB)
- Vanderbilt University Medical Center (US)
- Dartmouth College (US)
- University of Kentucky (US)
- Universitätsmedizin Göttingen (DE)
- Herlev Hospital (DK)
- Centre international de recherche sur le cancer (FR)
- Lund University (SE)
- National Cancer Institute (US)
- University of Washington (US)
- Harvard University (US)
- University of Sheffield (GB)
- University of Liverpool (GB)
- Umeå University (SE)
- Radboud University Medical Center (NL)
- BC Cancer Agency (CA)
- Washington State University Spokane (US)
- Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii USA
- Technion – Israel Institute of Technology (IL)
- German Cancer Research Center (DE)
- Moffitt Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Universidad de Oviedo (ES)
- National Institute of Occupational Health (NO)
- Nanjing Medical University (CN)
- Corresponding author
- Shen, Hongbing
- Amos, Christopher I.
- ORCID
- Zhou, Wen
- Liu, Geoffrey
- Hung, Rayjean J.
- Haycock, Philip C.
- Aldrich, Melinda C.
- Andrew, Angeline S.
- Arnold, Susanne M.
- Bickeböller, Heike
- Bojesen, Stig E.
- Brennan, Paul
- Brunnström, Hans
- Melander, Olle
- Caporaso, Neil E.
- Landi, Maria Teresa
- Chen, Chu
- Goodman, Gary E.
- Christiani, David C.
- Cox, Angela
- Field, John K.
- Johansson, Mikael
- Kiemeney, Lambertus A.
- Lam, Stephen
- Lazarus, Philip
- Rennert, Gad
- Risch, Angela
- Schabath, Matthew B.
- Shete, Sanjay S.
- Tardón, Adonina
- Zienolddiny, Shanbeh
- Shen, Hongbing
- Amos, Christopher I.
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2020-09-23
- Volume
- 148
- Issue
- 5
- Pages
- 1077-1086
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC7845289
- OpenAlex
- W3085547988
- Cited by
- 172
- References
- 53
- Citations by year
- 2026: 24 · 2025: 36 · 2024: 38 · 2023: 42 · 2022: 16 · 2021: 14 · 2020: 1
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Explore Bristol Research (acceptedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RR170048)
- Cancer Research UK (C18281, A19169)
- Foundation for the National Institutes of Health (CA164973, R01 CA111703, U01 CA167462, U01 CA209414, U01 CA6367307, U19 CA203654, UM1 CA167462)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- body mass index, smoking, lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, lung cancer histology, causal inference, reverse causality, confounding, obesity, lung carcinogenesis
- MeSH terms
- Humans, Lung Neoplasms, Obesity, Smoking, Body Mass Index, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Mendelian Randomization Analysis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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