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 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

Pharmaceutical Sciences

Nanjing Medical University
Baylor College of Medicine
University Health Network
University of Toronto
University of Bristol
Vanderbilt University
Dartmouth College
University of Kentucky
University of Göttingen
University of Copenhagen
International Agency for Research on Cancer
Lund University
National Institutes of Health
University of Washington
Harvard University
University of Sheffield
University of Liverpool
Umeå University
Radboud University Nijmegen
Provincial Health Services Authority
University of Hawai'i at Mānoa
Technion-Israel Institute of Technology
University of Salzburg
German Cancer Research Center
Member of the German Center for Lung Research (DZL)
Moffitt Cancer Center
University of Texas MD Anderson Cancer Center
University of Oviedo
National Institute of Occupational Health

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

145 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

Keywords

Mendelian randomization
body mass index
causal relationship
lung cancer
smoking phenotypes

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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

@article{5cdc77fa6bb24220a0b35caab8eb63fc,

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

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",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "John Wiley and Sons Inc",

number = "5",

}

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

TY - JOUR

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

UR - https://www.scopus.com/pages/publications/85091367419

U2 - 10.1002/ijc.33292

DO - 10.1002/ijc.33292

M3 - Article

C2 - 32914876

AN - SCOPUS:85091367419

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

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Keywords

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