Abstract
BACKGROUND: Previous observational studies have not clearly examined the impact of gastroesophageal reflux disease (GERD) on the risk of oral cavity and pharyngeal cancer (OCPC). To provide more evidence to elucidate this issue, we used Mendelian randomization (MR) to analyze the causal effect of GERD on OCPC and its subtypes. METHODS: We obtained the summary data of genome-wide association studies (GWAS) of European ancestry to perform MR analysis. GERD was considered the exposure, and OCPC (subtypes include oral cavity cancer (OCC) and oropharynx cancer (OPC)) was defined as the outcome. We aimed to investigate whether GERD has a causal effect on OCPC. We then attempted to obtain more accurate causal estimates by correcting for potential confounders such as smoking behavior, drinking behavior, body mass index (BMI), and type 2 diabetes (T2D). We also performed extensive sensitivity analyses to assess the robustness of the primary analysis results. RESULTS: Univariate MR analysis showed that GERD had a positive causal effect on OCPC (IVW: discovery, OR = 2.09 (95% CI 1.30-3.37), P = 0.0023; validation, OR = 1.90 (95% CI 1.26-2.87), P = 0.0020) and OCC (IVW: discovery, OR = 2.01 (95% CI: 1.21-3.33), P = 0.0066; validation, OR = 2.60 (95% CI 1.47-4.59), P = 0.0010). Although GERD increased the risk of OPC, this effect was statistically significant only in the discovery analysis (IVW: discovery, OR = 2.30 (95% CI 1.08-4.89), P = 0.0307; validation, OR = 1.15 (95% CI 0.67-1.97), P = 0.6199), the causal direction remained consistent. After adjusting for smoking, alcohol consumption, BMI, and T2D in multivariate analysis, the results remained largely consistent. CONCLUSIONS: Our study showed that GERD significantly increased the overall risk of OCPC, and similar results were found for its subtype OCC. This causal effect appears to be independent of cigarette use, drinking habits, BMI, and T2D. However, evidence for a causal effect of GERD on OPC is limited, and further research is expected to extend this finding. Future studies should explore the specific biological mechanisms through which GERD increases OCPC risk.