Causal effects of GERD on ENT disorders: a Mendelian randomization study

Abstract Objective Observational studies have linked gastroesophageal reflux disease (GERD) to various otolaryngologic diseases (ear, nose, and throat [ENT] disorders), but causal inference is limited by confounding and reverse causation. We used Mendelian randomization (MR) to evaluate causality while minimizing these biases. Methods MR analyses were conducted using genome-wide association study (GWAS) data from individuals of European ancestry. GERD data were derived from a meta-analysis of UK Biobank and QSKIN ( N = 602,604; cases = 129,080), and outcome data were obtained from FinnGen (outcome sample sizes ranged from 157,453 to 404,309). Six complementary MR methods (including IVW and MR-Egger) were applied to assess the causal effect of GERD on seven otolaryngologic diseases: allergic rhinitis (AR), chronic sinusitis (CRS), nasal polyps (NP), vocal cord dysfunction (VCD), sudden idiopathic hearing loss (SIHL), head and neck cancer (HNC), and thyroid carcinoma (THCA). After harmonization, the number of SNPs included in the analyses varied across outcomes, ranging from 65 to 75. Sensitivity analyses, including tests for heterogeneity, multiplicity, and leave-one-out analysis, were conducted to ensure robustness of the results. Results GERD was causally associated with an increased risk of AR–OR 1.17(95% CI 1.05–1.30), CRS–OR 1.25(95% CI 1.15–1.37), VCD–OR 1.52(95% CI 1.31–1.77), and SIHL–OR 1.38(95% CI 1.14–1.67). No causal effect was found for NP–OR 1.09(95% CI 0.95–1.25), HNC–OR 1.13(95% CI 0.90–1.42), or THCA–OR 1.07 (95% CI 0.83–1.39). Conclusion These results provide genetic evidence supporting a causal association between GERD and increased risks of AR, CRS, VCD, and SIHL. If validated in further studies, improved GERD prevention and management strategies could potentially reduce these risks.