Putative loss-of-function variants of Helicobacter pylori FecA2 are associated with reduced corpus atrophy and lower gastric cancer risk

Abstract Helicobacter pylori outer membrane proteins (OMPs) mediate host adaptation and virulence. While the iron-regulated OMP FecA2 facilitates environmental survival, the clinical impact of its genetic variation remains elusive. We investigated the association between fecA2 predicted loss-of-function variants and H. pylori -associated gastric disease severity. Clinical isolates were computationally profiled to identify fecA2 structural variants, while gastric mucosal atrophy was assessed using retrospective Updated Sydney System data. Utilizing Firth’s penalized logistic regression with robust internal validation, we found that the fecA2 predicted loss-of-function variant (Variant 2) exhibits a significant inverse association with disease severity. Compared to the wild-type, Variant 2 correlated with reduced gastric cancer risk (Adjusted OR = 0.34, 95% CI: 0.10–0.83, p = 0.024) and less severe mucosal atrophy expansion into the gastric corpus (Adjusted OR = 0.31, 95% CI: 0.14–0.63, p < 0.001), supported by stepwise depletion across severity scores (Trend p = 0.026). These findings indicate that fecA2 predicted loss-of-function mutations are linked to attenuated pathogenicity, restricted corpus atrophy, and lower gastric malignancy risk. Consequently, fecA2 represents a promising prognostic biomarker, though functional in vitro validation is necessary to elucidate the underlying mechanisms.