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Background Leveraging on the cluster-randomized, controlled trial: the Mass Intervention Trial in Linqu, Shandong Province (MITS, ChiCTR-TRC-10000979.), a large-scale community-based study enrolling 180,284 participants, we previously demonstrated that population-based Helicobacter pylori (H. pylori) screening and treatment constitutes an effective public health strategy for gastric cancer (GC) prevention. Building on this evidence, we further aimed to examine how H. pylori infection and anti-H. pylori treatment modifies incident GC risk, and to assess the effect modification by H. pylori virulence factors and host genetic susceptibility.Methods Based on post-unblinding data from the MITS (2011-2022), we designed a nested case-cohort study. Genetic analyses included 2804 participants (935 GC cases, 1869 subcohort participants), while combined analyses of genetic susceptibility and H. pylori seropositivity enrolled 2684 subjects (906 GC cases, 1778 subcohort participants). Plasma antibody responses against 12 H. pylori virulence factors were detected using the recomLine Helicobacter IgG 2.0 assay, and polygenic risk scores (PRSs) were calculated to evaluate host genetic susceptibility and to assess GC risk in relation to these factors.Results Elevated GC risk was observed among individuals seropositive for eight H. pylori virulence factors (CagA, VacA, GroEL, FliD, HpaA, HtrA, Omp, and HP0305). A protective effect of anti-H. pylori treatment was found in those seropositive for four key virulence factors (CagA, VacA, Omp, and HP0305) (IDDF2026-ABS-0437 Figure 1. Association between H. pylori seropositivity and GC risk). Among the high-genetic-risk group (top 20% of PRS), compared with H. pylori-positive individuals receiving symptom alleviation treatment, those receiving anti-H. pylori treatment showed a significantly reduced GC risk (HR=0.61, 95% CI:0.44-0.85); no such beneficial effect was found in the low-genetic-risk individuals (P-value-for-interaction=0.03) (IDDF2026-ABS-0437 Figure 2. GC risk after anti-H. pylori treatment by genetic risk stratification). Among individuals in the high-genetic-risk group who were seropositive for all four key virulence factors, anti-H. pylori treatment reduced GC risk by 59% (HR=0.41, 95% CI:0.19-0.90). (IDDF2026-ABS-0437 Figure 3. Anti-H. pylori treatment and GC risk by genetic risk stratification and number of seropositive key virulence factors).Conclusions The combination of key H. pylori virulence factors and genetic susceptibility can optimize the reception of anti-H. pylori treatment strategies for high-risk populations to prevent GCAbstract IDDF2026-ABS-0437 Figure 1Abstract IDDF2026-ABS-0437 Figure 2Abstract IDDF2026-ABS-0437 Figure 3