Genetic Susceptibility to Helicobacter pylori Infection and Pancreatic Cancer Risk: A Two-Sample Mendelian Randomisation Study

Background/Objectives: Pancreatic cancer is one of the most lethal malignancies, with poor survival and few established modifiable risk factors. While Helicobacter pylori (H. pylori) infection is a known cause of gastric cancer, its role in pancreatic cancer remains unclear, with inconsistent observational evidence. Methods: We applied two-sample Mendelian randomisation (2SMR) to assess the causal effect of H. pylori infection on pancreatic cancer risk. Genetic instruments were derived from GWAS data on anti-H. pylori IgG levels in the ALSPAC cohort (n = 4638). Outcomes were pancreatic cancer cases from UK Biobank (936 cases, 400,294 controls) and a combined dataset including UK Biobank, FinnGen, and MVP (5979 cases, 1,234,860 controls). Inverse-variance weighted (IVW) MR was the primary method, supported by MR-Egger, weighted median/mode and MR-PRESSO, with sensitivity analyses for pleiotropy. Results: Twelve and eleven independent SNPs explained 7.5% and 6.9% of H. pylori variance (mean F-statistics 22.37 and 22.42). No significant causal association was observed. IVW ORs were 1.039 (95% CI: 0.846–1.440, p = 0.466) for UK Biobank and 1.077 (95% CI: 0.962–1.206, p = 0.197) for the combined dataset. All complementary methods yielded null results, with no strong evidence of pleiotropy. Conclusions: This 2SMR study found no evidence that H. pylori infection causally increases pancreatic cancer risk. Larger studies with refined exposure measures are warranted.