Investigating Causal Effects of Hematologic Traits on Lung Cancer: A Mendelian Randomization Study

Abstract Background: Observational studies have suggested blood cell counts may act as predictors of cancer. It is not known whether these hematologic traits are causally associated with lung cancer. Methods: Two-sample bidirectional univariable Mendelian randomization (MR) and multivariable MR (MVMR) were performed to investigate the causal association between hematologic traits and the overall risk of lung cancer and three histologic subtypes [lung adenocarcinoma, squamous cell lung cancer, and small cell lung cancer (SCLC)]. The instrumental variables of 23 hematologic traits were strictly selected from large-scale genome-wide association studies. Inverse-variance weighted method and five extra methods were used to obtain robust causal estimates. Results: We found evidence that genetically influenced higher hematocrit [OR, 0.845; 95% confidence interval (CI), 0.783–0.913; P = 1.68 × 10−5] and hemoglobin concentration (OR, 0.868; 95% CI, 0.804–0.938; P = 3.20 × 10−4) and reticulocyte count (OR, 0.923; 95% CI, 0.872–0.976; P = 5.19 × 10−3) decreased lung carcinoma risk, especially in ever smokers. MVMR further identified hematocrit independently of smoking as an independent predictor. Subgroup analysis showed that a higher plateletcrit level increased the risk of small cell lung carcinoma (OR, 1.288; 95% CI, 1.126–1.474; P = 2.25 × 10−4). Conclusions: Genetically driven higher levels of reticulocyte count and hematocrit decreased lung cancer risk. Higher plateletcrit had an adverse effect on SCLC. Hematologic traits may act as low-cost factors for lung cancer risk stratification. Impact: Further studies are required to elucidate the potential mechanisms underlying the dysregulation of homeostasis related to hematologic traits, such as subclinical inflammation.