Abstract
BACKGROUND/AIMS: Gastrointestinal diseases present a significant global health challenge and greatly impact healthcare expenditures. Despite alcohol, tobacco, and coffee being universally recognized risk factors for various gastrointestinal disorders, the exact causal linkages have not been clarified because of the predominance of observational studies on this topic. Mendelian randomization (MR) was used to explore to what extent alcohol, tobacco, and coffee increase the risk of developing 13 upper and lower gastrointestinal diseases. METHODS: Genetic data from large genome-wide association studies including GSCAN, FinnGen, UK Biobank, IIBDGC, GERA, and other consortia were used for both univariable and multivariable MR analyses. Single-nucleotide polymorphisms were used as instrumental variables and sensitivity analyses were conducted to identify potential pleiotropic effects. RESULTS: Genetically predicted smoking was positively associated with esophageal cancer, Crohn's disease, gastric ulcer, irritable bowel syndrome, and gastroesophageal reflux risk, but was negatively associated with celiac disease risk. Alcohol intake was positively correlated with both esophageal cancer and chronic gastritis risk. These findings were confirmed by multivariable MR analyses, albeit with some variations. Coffee consumption was linked to esophageal cancer, but the association became nonsignificant after adjusting for hot beverage consumption. CONCLUSIONS: This comprehensive MR study suggests that alcohol and tobacco consumption are associated with the occurrence of several gastrointestinal diseases. These results support the need for public health initiatives to reduce smoking and alcohol abuse, with the aim of preventing both upper and lower gastrointestinal diseases.