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Background Helicobacter pylori (H. pylori) infects over 40% of the global population and is the primary risk factor for gastric cancer (GC). However, genome-wide evidence on host genetic susceptibility to H. pylori infection and its virulence factors in East Asian populations remains limited, and their shared genetic architecture with GC is unclear. We aimed to identify genetic variants associated with H. pylori infection and characterize their genetic overlap with GC.Methods We conducted two-stage genome-wide association studies (GWASs) for H. pylori infection and its virulence factors leveraging the Mass Intervention Trial in Linqu, Shandong Province (MITS; n=2804), with replication in the Upper Gastrointestinal Cancer Early Detection Program (UGCED; n=481). East Asian GC GWAS summary statistics (n=602,995) were used for cross-trait pleiotropy analyses, colocalization, and functional annotation. An Elastic Net-based Polygenic Risk Score for GC (ENPRSGC) integrating H. pylori- and GC-related PRSs was developed in MITS and validated in UGCED and UK Biobank (UKB; n=458,876), and further evaluated for progression of gastric lesion in the Shandong Intervention Trial (SIT; n=2,755).Results Eight H. pylori virulence factors were prospectively associated with GC risk. GWASs identified 83 variants associated with H. pylori infection and its virulence factors. Pleiotropy analyses revealed 160 shared variants between H. pylori and GC, with fine-mapping and colocalization prioritizing 17 regions harboring 16 candidate causal genes. A top candidate gene was supported by convergent evidence, including differential expression across gastric lesion stages and H. pylori virulence status, together with CRISPR dependency profiles (IDDF2026-ABS-0523 Figure 1). The ENPRSGC comprising 64 variants was associated with GC risk per SD increase in MITS (hazard ratio [HR]=1.23, 95% CI: 1.16-1.32) and UGCED (odds ratio [OR]=1.60, 95% CI: 1.19-2.15), with a stronger association for non-cardia GC. This association was further validated in the UKB cohort (HR=1.13, 95% CI: 1.03-1.24). ENPRSGC was also associated with gastric lesion progression in SIT (OR=1.10, 95% CI: 1.02-1.19).Conclusions Host genetic susceptibility to H. pylori infection and its virulence factors contribute to GC risk and share a common genetic basis with GC. A joint PRS incorporating H. pylori and GC genetic architecture improves GC risk stratification, supporting its potential for early identification of high-risk individuals.Abstract IDDF2026-ABS-0523 Figure 1