Mechanisms for the sex-specific effect of H. pylori on risk of gastroesophageal reflux disease and Barrett's oesophagus

Mechanisms for how Helicobacter pylori infection affects risk of gastroesophageal reflux disease (GERD) and Barrett's oesophagus (BE) are incompletely understood and might differ by sex. In a case-control study nested in the Melbourne Collaborative Cohort Study with 425 GERD cases and 169 BE cases (identified at 2007-10 follow-up), we estimated sex-specific odds ratios for participants who were H. pylori seronegative versus seropositive at baseline (1990-94). To explore possible mechanisms, we 1) compared patterns of H. pylori-induced gastritis by sex using serum pepsinogen-I and gastrin-17 data and 2) quantified the effect of H. pylori seronegativity on BE mediated by GERD using causal mediation analysis. For men, H. pylori seronegativity was associated with 1.69-fold (CI:1.03-2.75) and 2.28-fold (CI:1.27-4.12) higher odds of GERD and BE, respectively. No association was observed for women. H. pylori-induced atrophic antral gastritis was more common in men (68%) than in women (56%; p=0.015). For men, 5 of the 15 per 1,000 excess BE risk from being seronegative was mediated by GERD. Men, but not women, who were H. pylori seronegative had increased risks of GERD and BE. A possible explanation might be sex-differences in patterns of H. pylori-induced atrophic antral gastritis, which could lead to less erosive reflux for men. Evidence of GERD mediating the effect of H. pylori on BE risk among men supports this proposed mechanism. The findings highlight the importance of investigating sex differences in the effect of H. pylori on risk of GERD and BE in future studies.