Yuxin Ge, Xiaopan Lv, Dongxiao Hao, Rui Zhang, Yuanyuan Xin, Xuemin Yuan
Previous observational studies have suggested a potential causal relationship between Helicobacter pylori (H. pylori) infection and iron-deficiency anemia (IDA). However, the evidence for causal inference remains contentious, as observational studies are prone to confounding factors that may bias the results. Additionally, the mechanisms underlying the association between H. pylori infection and IDA remain incompletely elucidated. To address these gaps and delve deeper into the nature of the relationship between H. pylori and IDA, this study conducted a bidirectional two-sample Mendelian randomization (MR) analysis, which is less susceptible to confounding and reverse causality compared to traditional observational designs. Inverse-variance weighted (IVW) was used as the primary analytical method, with weighted median, MR-Egger regression, weighted mode, and simple mode as supplementary approaches. Seven common serum H. pylori antibodies were selected as exposure factors for the forward MR analysis. A series of sensitivity analyses was conducted to assess the reliability of the main MR assumptions and ensure the robustness of the study results. Reverse MR analysis was further performed to assess the potential reverse causality, and the results confirmed that there is no reverse causal relationship between IDA and H. pylori infection. Genetically predicted serum levels of H. pylori outer membrane protein (OMP) antibodies were positively associated with an increased risk of IDA (odds ratio [OR] = 1.077, 95% CI 1.010-1.148, P = 0.02194), while no causal association was observed for other antibodies. Reverse MR excluded reverse causality between IDA and H. pylori infection. This study first performed antibody-stratified two-sample MR analysis for seven H. pylori antibodies, suggesting that elevated OMP antibody levels increase IDA susceptibility and providing reliable causal evidence to enrich relevant research.