Dietary and metabolic factors contributing to Barrett’s esophagus: a univariate and multivariate Mendelian randomization study

Background Dietary and metabolic factors have been associated with the risk of Barrett’s esophagus (BE) in observational epidemiological studies. However, the aforementioned associations may be influenced by confounding bias. The present study aimed to evaluate these causal relationships through univariate and multivariate Mendelian randomization (MR) analysis. Methods Genetic instruments associated with dietary and metabolic factors were obtained in the large-scale genome-wide association studies (GWAS), respectively. Summary data for BE were available from a GWAS of 13,358 cases and 43,071 controls of European descent. Univariable MR analysis was initially performed to estimate the causal relationship between exposures and BE. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis. Multivariate MR analysis was further conducted to evaluate the independent effects of exposures on BE. Results In univariate MR analysis, BE was causally associated with higher body mass index (odds ratio (OR) = 2.575, 95% confidence interval (CI): 2.301-2.880, P = 7.369E-61), larger waist circumference (OR = 2.028, 95% CI: 1.648-2.496, P = 2.482E-11), and smoking per day (OR = 1.241, 95% CI: 1.085-1.419, P = 0.002). Dried fruit intake showed a protective effect on BE (OR = 0.228, 95% CI: 0.135-0.384, P = 2.783E-08), whereas alcohol drinking, coffee intake, tea intake, fresh fruit intake, and type 2 diabetes mellitus were not associated with BE (P = 0.351, P = 0.458, P = 0.125, P = 0.847, P = 0.413, respectively). No pleiotropy was found in the sensitivity analysis. The relationships of obesity, smoking, and dried fruit intake with BE risk remained strong after adjustment. Conclusions Our study provided MR evidence supporting obesity and smoking were independent risk factors for BE. Conversely, dried fruit intake was a protective factor for BE. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by a grant from the Science and Technology Program of Guangzhou, China (202206010103); and the Natural Science Foundation of Guangdong Province (2022A1515012469). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: https://gwas.mrcieu.ac.uk/ I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used in the present study were obtained from publicly available GWAS summary statistics, and the datasets presented in this study can be found in online repositories. * BE : Barrett’s esophagus GERD : gastroesophageal reflux disease EAC : esophageal adenocarcinoma T2DM : type 2 diabetes mellitus MR : Mendelian randomization SNPs : single nucleotide polymorphisms IVs : instrumental variables GWAS : genome□wide association study BMI : body mass index GIANT : Genetic Investigation of Anthropometric Traits GSCAN : GWAS and Sequencing Consortium of Alcohol and Nicotine use MRC-IEU : Medical Research Council-Integrative Epidemiology Unit LD : linkage disequilibrium MR-PRESSO : MR Pleiotropy RESidual Sum and Outlier IVW : inverse variance weighted OR : odds ratio CI : confidence interval