Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis
Shuai Yuan,
Jie Chen,
Xixian Ruan,
Yuhao Sun,
Ke Zhang,
Xiaoyan Wang,
Xue Li,
Dipender Gill,
Stephen Burgess,
Edward Giovannucci,
Susanna C Larsson
Affiliations
Shuai Yuan
School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China; Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China; Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China
Yuhao Sun
School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China
Ke Zhang
Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China
School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
Dipender Gill
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Edward Giovannucci
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States
Susanna C Larsson
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Background: Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Methods: Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Results: Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn’s disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. Conclusions: This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. Funding: The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.
