Smoking, Alcohol consumption, and 24 Gastrointestinal Diseases: Mendelian Randomization Analysis

  1. Shuai Yuan
  2. Jie Chen
  3. Xixian Ruan
  4. Yuhao Sun
  5. Ke Zhang
  6. Xiaoyan Wang  Is a corresponding author
  7. Xue Li  Is a corresponding author
  8. Dipender Gill
  9. Stephen Burgess
  10. Edward Giovannucci
  11. Susanna C Larsson
  1. Karolinska Institute, Sweden
  2. Second Affiliated Hospital of Zhejiang University, China
  3. Central South University, China
  4. Westlake University, China
  5. Zhejiang University, China
  6. Imperial College London, United Kingdom
  7. University of Cambridge, United Kingdom
  8. 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.

The following previously published data sets were used

Article and author information

Author details

  1. Shuai Yuan

    Institute of Environmental Medicine, Karolinska Institute, Solna, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  2. Jie Chen

    Second Affiliated Hospital of Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4029-4192
  3. Xixian Ruan

    Department of Gastroenterology, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4937-9168
  4. Yuhao Sun

    Second Affiliated Hospital of Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Ke Zhang

    Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, Westlake University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaoyan Wang

    Department of Gastroenterology, Central South University, Changsha, China
    For correspondence
    wangxiaoyan@csu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7281-1078
  7. Xue Li

    Usher Institute, Zhejiang University, Hangzhou, China
    For correspondence
    xue.li@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6880-2577
  8. Dipender Gill

    Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Stephen Burgess

    MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5365-8760
  10. Edward Giovannucci

    Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Susanna C Larsson

    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

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

  1. 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

  1. Received: October 8, 2022
  2. Accepted: February 1, 2023
  3. Accepted Manuscript published: February 2, 2023 (version 1)
  4. 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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  1. Shuai Yuan
  2. Jie Chen
  3. Xixian Ruan
  4. Yuhao Sun
  5. Ke Zhang
  6. Xiaoyan Wang
  7. Xue Li
  8. Dipender Gill
  9. Stephen Burgess
  10. Edward Giovannucci
  11. Susanna C Larsson
(2023)
Smoking, Alcohol consumption, and 24 Gastrointestinal Diseases: Mendelian Randomization Analysis
eLife 12:e84051.
https://doi.org/10.7554/eLife.84051

Share this article

https://doi.org/10.7554/eLife.84051

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