Dissecting the Causal Effects of Helicobacter pylori Serotypes on Gastric Cancer Risk: A Two-Sample Mendelian Randomization Study

Background Although Helicobacter pylori infection is a primary risk factor for gastric cancer (GC), the specific bacterial components that causally drive carcinogenesis remain poorly understood. Traditional epidemiological studies are limited by confounding variables and the potential for reverse causation. This study aimed to dissect the causal effects of host antibody responses to various H. pylori antigens on GC risk using Mendelian randomization (MR). Methodology We conducted a two-sample MR study using summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry populations. Genetic instruments were selected for general H. pylori seropositivity and antibody levels against six antigens: cytotoxin-associated gene A (CagA), Catalase, GroEL, outer membrane protein (OMP), urease subunit A (UreA), and vacuolating cytotoxin A (VacA). The primary outcome was GC. Inverse-variance weighted (IVW) MR served as the main analysis, with comprehensive sensitivity analyses to assess the robustness of results. Multivariable MR (MVMR) was used to estimate the direct effects of each serotype, and a two-step mediation analysis was performed to explore potential mediating pathways. Results Genetically predicted general H. pylori seropositivity was causally associated with an increased risk of GC (odds ratio (OR): 1.12, 95% confidence interval (CI): 1.01-1.24; P = 0.027). The host antibody response to OMP showed a stronger causal effect (OR: 1.19, 95% CI: 1.08-1.30; P < 0.001). In contrast, no causal effects were observed for antibody responses to the classic virulence factors CagA or VacA (P > 0.05). In multivariable analysis, the effect of the anti-OMP response remained robust (OR: 1.18, 95% CI: 1.07-1.30; P = 0.001), while the association for general seropositivity was attenuated to null. Mediation analysis implicated tumor necrosis factor ligand superfamily member 18 (TNFSF18) as a potential mediator of the H. pylori-GC pathway, accounting for a substantial portion of the total effect (estimated at 47.0%), though this finding did not reach statistical significance (P = 0.077). Conclusions This MR study provides genetic evidence that the host immune response to H. pylori OMPs, rather than to classic virulence factors like CagA, is a key contributor to gastric carcinogenesis. This effect appears to be partially mediated by the inflammatory TNFSF18 pathway, suggesting that the chronic host-bacterial interactions at the gastric epithelial surface are critical to malignant transformation.