Genetic evidence for associations between gastroesophageal reflux disease and site-specific extraesophageal cancers

Observational studies have suggested an increased risk of extraesophageal cancers in patients with gastroesophageal reflux disease (GERD), but whether these associations are causal remains uncertain. This study systematically evaluated the potential associations between genetically predicted GERD and 22 extraesophageal cancers. Genetic instruments for GERD were obtained from a large genome-wide association study including 129,080 cases and 473,524 controls. Outcome data for 22 site-specific extraesophageal cancers were obtained from multiple genome-wide association study datasets, including the UK Biobank, FinnGen, and international cancer consortia. Two-sample Mendelian randomization (MR) analyses were performed, and dataset-specific MR estimates were subsequently combined using meta-analysis. For positive findings, reverse MR and Multivariable Mendelian randomization analyses were further conducted to assess causal direction and independence from body mass index, smoking intensity, and alcohol consumption. Meta-analysis of two-sample MR showed Bonferroni-significant positive associations of genetically predicted GERD with lung cancer (odds ratio [OR] = 1.220; 95% confidence interval [CI]: 1.100–1.354; P  = .0002) and pancreatic cancer (OR = 1.517; 95% CI: 1.214–1.895; P  = .0002). Suggestive positive associations were also observed for laryngeal cancer (OR = 1.774; 95% CI: 1.091–2.884; P  = .021) and bladder cancer (OR = 1.254; 95% CI: 1.047–1.501; P  = .014), although neither survived Bonferroni correction. In Multivariable Mendelian randomization analyses accounting for body mass index, smoking intensity, and alcohol consumption, the association with lung cancer remained statistically significant (OR = 1.190; 95% CI: 1.040–1.362; P  = .012), whereas the associations with pancreatic, laryngeal, and bladder cancers were no longer statistically significant. These findings provide genetic evidence supporting an association between genetically predicted GERD and lung cancer. The evidence for pancreatic, laryngeal, and bladder cancers was less robust and requires further validation in larger independent datasets. These findings may help prioritize future research on cancer risk among individuals with GERD, with further studies warranted to validate the observed associations and clarify their underlying mechanisms.