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 (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.

Keywords: Mendelian randomization; body mass index; causal relationship; lung cancer; smoking phenotypes.

FIGURE 1

Illustration of the total effect and direct effect of BMI on lung cancer. The direct effect of BMI on lung cancer is the effect BMI has on lung cancer not via any other exposure variables, which equal to β_XZ. The total effect of BMI on lung cancer is the effect of BMI on lung cancer directly plus the effect of BMI on lung cancer via smoking, which is equal to β_XZ + α_XYβ_YZ. BMI, body mass index

FIGURE 2

Odds ratios (ORs) and 95% confidence intervals (CIs) for the effect of BMI and smoking phenotypes on lung cancer and histological subtypes estimated using the multivariable Mendelian randomization (MR) inverse-variance weighted approach. Adeno: lung adenocarcinoma; Overall: overall lung cancer; Small: small cell lung cancer; Squam: lung squamous cell carcinoma. Colors indicate five exposures. BMI, body mass index; SmkInit, smoking status; AgeSmk, age of smoking initiation; SmkCes, smoking cessation; CigDay, cigarettes per day. For example, there were 776 BMI-associated SNPs used in multivariable MR jointly with other smoking-associated SNPs to investigate their causal effects on overall lung cancer. No significant effect of BMI on overall lung cancer was observed (OR = 0.95, 95% CI = 0.87–1.03, P = .224)