Genome-wide association and Mendelian randomization analyses of host response to Helicobacter pylori infection implicate HLA polymorphisms and immune-mediated diseases

Helicobacter pylori (H. pylori) infects the gastric epithelium of approximately half of the global population, and is a well-known risk factor for developing gastric cancer. Despite the clinical significance of H. pylori infection, many genetic factors underlying host response to H. pylori remain unidentified. Moreover, although H. pylori infection has been implicated in a range of extra-gastric diseases, whether these associations share a common genetic architecture remains unclear. We performed a genome-wide association study (GWAS) of anti-H. pylori IgG antibody titers, a composite host phenotype reflecting susceptibility to persistent infection and subsequent immune activation, followed by gene-based and pathway analyses, involving up to 140,863 individuals. This included 56,967 individuals in the discovery phase and 68,211 in the replication phase from Japanese cohorts, together with an additional 15,685 from European populations in a cross-ancestry meta-analysis. We reveal significant associations between IgG titers and polymorphisms in the Human Leukocyte Antigen (HLA) class II region within the Major Histocompatibility Complex (MHC), as well as genes related to innate immunity, including CCDC80, NFKBIZ, TIFA, PSCA, and TRAF3. Mendelian randomization (MR) analyses revealed directionally consistent associations between genetic liability to higher anti-H. pylori IgG levels and a range of diseases, including immune-mediated diseases such as type 1 diabetes, Hashimoto's disease, atopic dermatitis, as well as quantitative traits like body height and weight. These genetic findings support the interpretation that host genetic determinants of response to H. pylori, particularly those mediated through HLA class II, form part of a shared immunogenetic architecture associated with susceptibility to multiple immune-related diseases.