Lifestyle Factors Drive Risk Stratification in Barrett’s Esophagus, While Polygenic Risk Scores Add No Incremental Predictive Value: Results of the BarrettNET Cohort

Barrett's esophagus is the established precursor of gastroesophageal adenocarcinoma, yet most cases are diagnosed outside surveillance. The study investigated demographic, life-style, and genetic contributions to disease stage and progression Barrett's esophagus. Data from 870 participants in the prospective, multicenter BarrettNET registry (10-year follow-up period) were analyzed. Epidemiological data (smoking, alcohol, physical activity, diet, BMI, reflux symptoms) were collected via standardized questionnaires; dietary quality was assessed with a validated nutrition score. Multivariable logistic regression identified factors associated with advanced disease at diagnosis (non-dysplastic disease versus dysplasia or cancer); progression was evaluated using Firth penalized logistic regression. In a genotyped subgroup (739 participants), weighted polygenic risk scores from 41 variants were included as a sensitivity analysis. Among 598 patients with non-dysplastic disease, 116 with dysplasia, and 156 with cancer, older age (OR 1.03, 95% CI 1.01-1.04), male sex (OR 1.92, 95% CI 1.28-2.90), and smoking (OR 1.64, 95% CI 1.15-2.35) were associated with advanced disease. Of 21 participants who progressed during follow-up, older age (OR 1.06, 95% CI 1.02-1.11) and smoking (OR 4.31, 95% CI 1.62-11.47) were associated with progression, whereas reflux symptoms were associated with lower odds (OR 0.36, 95% CI 0.15-0.84; apparent AUC 0.825). Dietary factors and polygenic risk scores showed no independent association with either outcome and did not improve prediction. Age, male sex, and smoking predicted advanced disease and progression in Barrett's esophagus, while currently available polygenic risk scores added little predictive value, supporting lifestyle-based approaches to risk stratification.