Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization
Wen Zhou, Geoffrey Liu, Rayjean J. Hung, Philip 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, Loı̈c Le Marchand, Gad Rennert, Angela Risch, Matthew B. Schabath, Sanjay Shete, Adonina Tardón, Shanbeh Zienolddiny, Hongbing Shen, Christopher I. Amos
Abstract
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.