Effect of smoking-related features and 731 immune cell phenotypes on esophageal cancer: a two-sample and mediated Mendelian randomized study

Introduction: Numerous observational studies have indicated that smoking is a substantial risk factor for esophageal cancer. However, there is a shortage of research that delves into the specific causal relationship and potential mediators between the two. Our study aims to validate the correlation between smoking-related traits and esophageal cancer while exploring the possible mediating effects of immune factors. Methods: Initially, we conducted bidirectional univariate Mendelian Randomization (MR) analyses to forecast the causal effects linking smoking-related traits and esophageal cancer. Subsequently, we employed a two-step MR analysis to scrutinize immune cell phenotypes that could mediate these effects. Finally, the coefficient product method was employed to determine the precise mediating impact. Additionally, we have refined our sensitivity analysis to ensure the reliability of the outcomes. Results: After analysis, Smoking status: Never had a significant negative association with the incidence of esophageal cancer (inverse-variance weighted (IVW) method, p=1.82e-05, OR=0.10, 95%CI=0.04 similar to 0.29). Ever smoked (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33 similar to 13.94) and Current tobacco smoking (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33 similar to 13.94) showed the promoting effect on the pathogenesis of esophageal cancer. Through further examination, researchers discovered 21 immune cell phenotypes that have a causal relationship with esophageal cancer. After careful screening, two immune cell phenotypes were found to have potential mediating effects. In particular, it was observed that in the case of the preventive effect of Smoking status: Never on esophageal cancer, the absolute count of CD62L plasmacytoid dendritic cells mediated a reduction of 4.21%, while the mediating effect of CD27 in CD20-CD38-B cells was -4.12%. In addition, sensitivity analyses did not reveal significant heterogeneity or level pleiotropy. Conclusion: The study provides new evidence for the causal relationship between smoking-related features and esophageal cancer and proposes immune factors with potential mediating effects. However, this finding needs to be further demonstrated by more extensive clinical studies.