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

Wen Zhou; Geoffrey Liu; Rayjean J. Hung; Philip C. Haycock; Melinda C. Aldrich; Angeline S. Andrew; Susanne M. Arnold; Heike Bickeböller; Stig E. Bojesen; 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

doi:10.1002/ijc.33292

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

Wen Zhou, Geoffrey Liu, Rayjean J. Hung, Philip C. Haycock, Melinda C. Aldrich, Angeline S. Andrew, Susanne M. Arnold, Heike Bickeböller, Stig E. Bojesen, 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 JohanssonLambertus 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

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1077-1086
Number of pages	10
Journal	International Journal of Cancer
Volume	148
Issue number	5
DOIs	https://doi.org/10.1002/ijc.33292
State	Published - Mar 1 2021

Bibliographical note

Publisher Copyright:
© 2020 UICC

Funding

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. 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. 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

Funders	Funder number
International Agency for Research on Cancer/World Health Organization
NCI/NIH
National Institutes of Health/National Cancer Institute
National Institutes of Health (NIH)	U01 CA6367307, UM1 CA167462, CA164973, R01 CA111703
National Institutes of Health (NIH)
U.S. Department of Health and Human Services
National Childhood Cancer Registry – National Cancer Institute	R35CA197449, U01 CA209414, U19 CA203654
National Childhood Cancer Registry – National Cancer Institute
Cancer Prevention and Research Institute of Texas	RR170048
Cancer Prevention and Research Institute of Texas
National Cancer Institute Division of Cancer Epidemiology and Genetics
Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre	C18281, C18281/A19169, A19169
Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre
National Cancer Institute, Cairo University
China Scholarship Council
Nanjing Medical University

Keywords

Mendelian randomization
body mass index
causal relationship
lung cancer
smoking phenotypes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ijc.33292

Cite this

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., ... Amos, C. I. (2021). Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization. International Journal of Cancer, 148(5), 1077-1086. https://doi.org/10.1002/ijc.33292

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abstract = "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.",

keywords = "Mendelian randomization, body mass index, causal relationship, lung cancer, smoking phenotypes",

author = "Wen Zhou and Geoffrey Liu and Hung, {Rayjean J.} and Haycock, {Philip C.} and Aldrich, {Melinda C.} and Andrew, {Angeline S.} and Arnold, {Susanne M.} and Heike Bickeb{\"o}ller and Bojesen, {Stig E.} and Paul Brennan and Hans Brunnstr{\"o}m and Olle Melander and Caporaso, {Neil E.} and Landi, {Maria Teresa} and Chu Chen and Goodman, {Gary E.} and Christiani, {David C.} and Angela Cox and Field, {John K.} and Mikael Johansson and Kiemeney, {Lambertus A.} and Stephen Lam and Philip Lazarus and {Le Marchand}, Lo{\"i}c and Gad Rennert and Angela Risch and Schabath, {Matthew B.} and Shete, {Sanjay S.} and Adonina Tard{\'o}n and Shanbeh Zienolddiny and Hongbing Shen and Amos, {Christopher I.}",

note = "Publisher Copyright: {\textcopyright} 2020 UICC",

year = "2021",

month = mar,

day = "1",

doi = "10.1002/ijc.33292",

language = "English",

volume = "148",

pages = "1077--1086",

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Zhou, W, Liu, G, Hung, RJ, Haycock, PC, Aldrich, MC, Andrew, AS, Arnold, SM, Bickeböller, H, Bojesen, SE, Brennan, P, Brunnström, H, Melander, O, Caporaso, NE, Landi, MT, Chen, C, Goodman, GE, Christiani, DC, Cox, A, Field, JK, Johansson, M, Kiemeney, LA, Lam, S, Lazarus, P, Le Marchand, L, Rennert, G, Risch, A, Schabath, MB, Shete, SS, Tardón, A, Zienolddiny, S, Shen, H & Amos, CI 2021, 'Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization', International Journal of Cancer, vol. 148, no. 5, pp. 1077-1086. https://doi.org/10.1002/ijc.33292

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T1 - Causal relationships between body mass index, smoking and lung cancer

T2 - Univariable and multivariable Mendelian randomization

AU - Zhou, Wen

AU - Liu, Geoffrey

AU - Hung, Rayjean J.

AU - Haycock, Philip C.

AU - Aldrich, Melinda C.

AU - Andrew, Angeline S.

AU - Arnold, Susanne M.

AU - Bickeböller, Heike

AU - Bojesen, Stig E.

AU - Brennan, Paul

AU - Brunnström, Hans

AU - Melander, Olle

AU - Caporaso, Neil E.

AU - Landi, Maria Teresa

AU - Chen, Chu

AU - Goodman, Gary E.

AU - Christiani, David C.

AU - Cox, Angela

AU - Field, John K.

AU - Johansson, Mikael

AU - Kiemeney, Lambertus A.

AU - Lam, Stephen

AU - Lazarus, Philip

AU - Le Marchand, Loïc

AU - Rennert, Gad

AU - Risch, Angela

AU - Schabath, Matthew B.

AU - Shete, Sanjay S.

AU - Tardón, Adonina

AU - Zienolddiny, Shanbeh

AU - Shen, Hongbing

AU - Amos, Christopher I.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

AB - 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.

KW - Mendelian randomization

KW - body mass index

KW - causal relationship

KW - lung cancer

KW - smoking phenotypes

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DO - 10.1002/ijc.33292

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SN - 0020-7136

VL - 148

SP - 1077

EP - 1086

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 5

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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