Causal Role of Immune Cells in Gastric Cancer: A Mendelian Randomisation (MR) Study

Abstract

Background: Observational studies have reported an association between immune cells and digestive diseases. We sought to assess the relationship between immune cells and the risk of gastric malignancy by two-way two-sample Mendelian randomisation (MR) analysis. Methods: This study used a comprehensive two-sample Mendelian randomisation (MR) analysis to determine the causal relationship between immune cells and gastric malignancy (GC). Based on publicly available genetic data, we explored the causal relationship between 731 immune cell signatures and GC risk. We performed Mendelian randomisation (MR) analyses using genetic variants strongly associated with neutrophil, lymphocyte, eosinophil, basophil and monocyte counts as instrumental variables (IVs). Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity and horizontal pleiotropy of the results. Results: Two-sample MR analysis revealed that multiple immune cell phenotypes were significantly associated with the risk of gastric malignancy. Among the phenotypes with low uncorrected p-values, including CD14- CD16- AC (p < 0.001; OR = 0.9730; 95% CI = 0.9598–0.9863); DN (CD4- CD8-) AC (p < 0.001; OR = 1.1483; 95% CI = 1.0607–1.2432); IgD on IgD+ (p < 0.001; OR = 0.8883; 95% CI = 0.8289–0.9520). Meanwhile, we used Simple mode, Weight median, and Weight mode, all of which led to the same conclusion. Moreover, in our further analysis, gastric malignancy also had a causal effect on the above immune cell types when gastric malignancy was used as an exposure factor, and the results were statistically significant. Conclusion: The study underscores the crucial role of immune cells in GC development, providing key insights for future research. The statistically significant associations between specific immune cell phenotypes and gastric malignancy risk highlight potential targets for therapeutic interventions aimed at modulating the immune response in GC, thereby opening avenues for precision medicine approaches in the treatment of this disease.