Causal Relationship between Chronic Gastritis and Sleep Apnea Syndrome: A Bidirectional and Two-step Mendelian Randomization Study

Background: Sleep apnea syndrome (SAS) and chronic gastritis are prevalent in middle-aged and elderly people. Although clinical observations suggest an association between the two diseases, the causal relationship between them has not been clarified. This study aims to explore the causal relationship between SAS and chronic gastritis and to elucidate the possible mediating mechanisms. Methods: The causal relationship between SAS and chronic gastritis was assessed using five methods, primarily utilizing the Inverse Variance Weighted (IVW) approach, with other methods categorized as sensitivity analyses. A two-step Mendelian randomization study was conducted using a genome-wide association study (GWAS) dataset to evaluate the mediating role of signatures in immune cell and inflammatory proteins. Sensitivity analyses were conducted to determine the robustness of the results. To systematically address horizontal pleiotropy, we employed the CAUSE framework, which distinguishes causal effects from confounding by comparing genetic architectures under competing causal and shared confounding models, while accounting for both linkage disequilibrium-related and independent pleiotropic pathways. The STROBE-MR guidelines were followed for MR results reporting. Results: Through two-sample MR analysis, we identified significant bidirectional causal relationships between sleep apnea syndrome (SAS) and chronic gastritis (forward: OR = 1.131, 95% CI: 1.031-1.240, p = 0.009; reverse: OR = 1.065, 95% CI: 1.007-1.128, p = 0.028). Simulation studies confirmed CAUSE's superior specificity in controlling false positives through its dual-model framework that explicitly accounts for pleiotropic pathways. Two-step MR analysis revealed that the changes in the level of PD-L1 expressed by CD14+CD16+ monocytes played a significant mediating role in the effect of chronic gastritis on SAS. Conclusion: The bidirectional causal relationship between SAS and chronic gastritis was confirmed through two-sample and two-step MR analyses. Chronic gastritis may increase the risk of SAS through genetic signatures in immune cells, providing new perspectives for future research and aiding in the development of new prevention and treatment strategies.