Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization

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  • Wen Zhou
  • Geoffrey Liu
  • Rayjean J. Hung
  • Philip C. Haycock
  • Melinda C. Aldrich
  • Angeline S. Andrew
  • Susanne M. Arnold
  • Heike Bickeböller
  • Paul Brennan
  • Hans Brunnström
  • Olle Melander
  • Neil E. Caporaso
  • Maria Teresa Landi
  • Chu Chen
  • Gary E. Goodman
  • David C. Christiani
  • Angela Cox
  • John K. Field
  • Mikael Johansson
  • Lambertus A. Kiemeney
  • Stephen Lam
  • Philip Lazarus
  • Loïc Le Marchand
  • Gad Rennert
  • Angela Risch
  • Matthew B. Schabath
  • Sanjay S. Shete
  • Adonina Tardón
  • Shanbeh Zienolddiny
  • Hongbing Shen
  • Christopher I. Amos

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 (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR =.011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR =.008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR =.036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR =.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.

Original languageEnglish
JournalInternational Journal of Cancer
Volume148
Issue number5
Pages (from-to)1077-1086
ISSN0020-7136
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
Dr. Amos is a research scholar of the Cancer Prevention Research Institute of Texas (CPRIT). His research is partially funded by CPRIT grant RR170048 and by NIH/NCI grant U19CA203654. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. The Boston Lung Cancer Study was funded by NIH (NCI) U01CA209414 (PI: Christiani). The EAGLE study was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The Multiethnic Cohort Study is supported by the National Institutes of Health (CA164973). The CARET study was supported by the National Institutes of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), U01CA6367307 (PIs: Omen, Goodman), R01 CA111703 (PI: Chen) and U01 CA167462 (PI: Chen). Philip C Haycock is supported by Cancer Research UK (C18281/A19169). Wen Zhou was supported by China Scholarship Council and Nanjing Medical University.

Funding Information:
Dr. Amos is a research scholar of the Cancer Prevention Research Institute of Texas (CPRIT). His research is partially funded by CPRIT grant RR170048 and by NIH/NCI grant U19CA203654. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. The Boston Lung Cancer Study was funded by NIH (NCI) U01CA209414 (PI: Christiani). The EAGLE study was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS. The Multiethnic Cohort Study is supported by the National Institutes of Health (CA164973). The CARET study was supported by the National Institutes of Health/National Cancer Institute: UM1 CA167462 (PI: Goodman), U01CA6367307 (PIs: Omen, Goodman), R01 CA111703 (PI: Chen) and U01 CA167462 (PI: Chen). Philip C Haycock is supported by Cancer Research UK (C18281/A19169). Wen Zhou was supported by China Scholarship Council and Nanjing Medical University.

Funding Information:
Cancer Prevention and Research Institute of Texas, Grant/Award Number: RR170048; Cancer Research UK, Grant/Award Numbers: C18281, A19169; Foundation for the National Institutes of Health, Grant/Award Numbers: CA164973, R01 CA111703, U01 CA167462, U01 CA209414, U01 CA6367307, U19 CA203654, UM1 CA167462 Funding information F TS

Publisher Copyright:
© 2020 UICC

    Research areas

  • body mass index, causal relationship, lung cancer, Mendelian randomization, smoking phenotypes

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