Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study

OBJECTIVE: We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS: Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A(1c) (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS: Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03–1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07–1.17) for gastric ulcer, 1.11 (95% CI, 1.03–1.20) for acute gastritis, 1.07 (95% CI, 1.01–1.13) for chronic gastritis, 1.08 (95% CI, 1.03–1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01–1.07) for diverticular disease, 1.08 (95% CI, 1.02–1.14) for acute pancreatitis, 1.09 (95% CI, 1.05–1.12) for cholelithiasis, 1.09 (95% CI, 1.05–1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17–1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03–1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89–0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS: Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.