Smoking, Alcohol consumption, and 24 Gastrointestinal Diseases: Mendelian Randomization Analysis
- Karolinska Institute, Sweden
- Second Affiliated Hospital of Zhejiang University, China
- Central South University, China
- Westlake University, China
- Zhejiang University, China
- Imperial College London, United Kingdom
- University of Cambridge, United Kingdom
- Harvard TH Chan School of Public Health, United States
Abstract
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, acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 21 associations persisted after adjusting for genetically-predicted alcohol consumption. Genetically-predicted higher alcohol consumption was associated with increased risk of duodenal cancer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain after adjustment for genetic predisposition to smoking initiation.
Conclusion: 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.
Data availability
Data analyzed in the current study are publicly available GWAS summary-level data. The specific information and link could be found in Table S1. The code and curated data for the current analysis are available at https://github.com/XixianRuan/smoking_gi.
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Data Related to Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol useGWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN).
Article and author information
Author details
Funding
National Natural Science Foundation of China (81970494)
- Xiaoyan Wang
Key Project of Research and Development Plan of Hunan Province (2019SK2041)
- Xiaoyan Wang
Hjärt-Lungfonden (20210351)
- Susanna C Larsson
Vetenskapsrådet (2019-00977)
- Susanna C Larsson
Cancerfonden
- Susanna C Larsson
Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001)
- Xue Li
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joris Deelen, Max Planck Institute for Biology of Ageing, Germany
Ethics
Human subjects: Included studies had been approved by corresponding institutional review boards and ethical committees, and consent forms had been signed by all participants.
Version history
- Received: October 8, 2022
- Accepted: February 1, 2023
- Accepted Manuscript published: February 2, 2023 (version 1)
- Version of Record published: March 15, 2023 (version 2)
Copyright
© 2023, Yuan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Smoking, Alcohol consumption, and 24 Gastrointestinal Diseases: Mendelian Randomization Analysis
eLife 12:e84051.
https://doi.org/10.7554/eLife.84051
Further reading
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- Epidemiology and Global Health
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- Epidemiology and Global Health
Background:
Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.
Methods:
We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.
Results:
Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.
Conclusions:
Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.
Funding:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
