Does Increased Muscle Mass Associate with Reduced Small Cell Lung Cancer Risk? Evidence from a Mendelian Randomization Study

Abstract Observational studies suggest an association between reduced appendicular lean mass and increased lung cancer risk, but confounding biases exist. This study aimed to investigate the causal relationship between appendicular lean mass and small cell lung cancer risk using Mendelian randomization analysis. A two-sample Mendelian randomization study was conducted using summary-level data from genome-wide association studies on appendicular lean mass (205,513 Europeans) as exposure and small cell lung cancer (174,006 Europeans) as the outcome. 251 genetic variants robustly associated with appendicular lean mass were selected as instrumental variables. Inverse-variance weighted, MR-Egger regression, and other methods were used to estimate causality. The inverse-variance weighted method provided evidence for a causal association between increased appendicular lean mass and reduced small cell lung cancer risk (OR 0.530, 95% CI 0.305–0.923, P = 0.026). Sensitivity analyses indicated no pleiotropy or heterogeneity. Increased appendicular lean mass appears causally associated with reduced small cell lung cancer risk, adding credibility to previous observational evidence. These findings provide preliminary insight into lung cancer pathogenesis and prevention from a nutritional and metabolic perspective. Further research is warranted to elucidate underlying mechanisms.