Gastric cancer risk associated with autoimmune gastritis-predisposing HLA alleles: a national prospective cohort study

Background: The link between autoimmune gastritis (AIG) and gastric cancer (GC) remains debated, hampered by diagnostic challenges and confounding factors like Helicobacter pylori . AIG-predisposing Human leukocyte antigen (HLA) alleles offer a genetic proxy to investigate this relationship. Methods: 439 828 UK Biobank participants with HLA genotypes were enrolled. Exposure was defined as carriage of established AIG-associated HLA alleles. The primary outcome was incident GC. Cox proportional hazards models assessed associations, adjusting for demographics, lifestyle, ancestry, H. pylori , and precancerous lesions. Multiplicative interactions between alleles and comorbid conditions were tested. Results: Over a median of 13.27 years follow-up, 904 incident GC cases occurred. In the fully adjusted model, HLA-DRB1*04:07 (HR: 1.55, 95% CI: 1.04–2.31), DRB1*04:10 (14.13, 1.95–102.32), and DQB1*03:04 (2.79, 1.25–6.23) were nominally associated with elevated GC risk. Notably, HLA-DQB1*03:04 remained significant after FDR correction. Compared with individuals without polyps or benign neoplasms, the association between DQB1*03:04 and GC was more pronounced among those with polyps (HR = 16.57) and benign neoplasms (HR = 25.72). Conclusion: Specific AIG-predisposing HLA alleles were identified as risk factors for GC, independent of H. pylori . The interaction between DQB1*03:04 and precancerous lesions suggests high-risk subgroups warranting intensified surveillance. HLA genotyping may help identify individuals at elevated GC risk, particularly among those with polyps or benign neoplasms.