1. Epidemiology and Global Health
  2. Genetics and Genomics

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. School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, China
  2. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden
  3. Department of Gastroenterology, The Third Xiangya Hospital, Central South University, China
  4. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, China
  5. Westlake Intelligent Biomarker Discovery Lab, Westlake Laboratory of Life Sciences and Biomedicine, China
  6. Centre for Global Health Research, Usher Institute, University of Edinburgh, United Kingdom
  7. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom
  8. MRC Biostatistics Unit, University of Cambridge, United Kingdom
  9. Department of Public Health and Primary Care, University of Cambridge, United Kingdom
  10. Department of Epidemiology, Harvard T.H. Chan School of Public Health, United States
  11. Department of Nutrition, Harvard T.H. Chan School of Public Health, United States
  12. Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Sweden
https://doi.org/10.7554/eLife.84051
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Cite this article
  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
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2 figures, 2 tables and 3 additional files

Figures

Figure 1
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Overview of the present study design.

GERA, Genetic Epidemiology Research on Aging; IIBDGC, the International Inflammatory Bowel Disease Genetics Consortium; MR, Mendelian randomization; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; SNP, single nucleotide polymorphism.

Figure 2
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Summary of associations of genetically predicted smoking initiation, lifetime smoking, and alcohol consumption with 24 gastrointestinal diseases.

UVMR, univariable Mendelian randomization; MVMR, multivariable Mendelian randomization. The numbers in the box are the odds ratios for associations of exposure for gastrointestinal diseases. The association with a p-value <0.05 but Benjamini-Hochberg adjusted p-value >0.05 was regarded suggestive, and the association with a Benjamini-Hochberg adjusted p-value <0.05 was deemed significant.

Tables

Table 1
Associations of genetic predisposition to smoking initiation with 24 gastrointestinal diseases in univariable and multivariable Mendelian randomization analyses.
DiseaseTotal casesTotal controlsUVMRMVMR adjusted for alcohol consumption
OR (95% CI)p ValueI2 (95% CI)OR (95% CI)p Value
Upper gastrointestinal diseasesGastroesophageal reflux34,135634,6291.28 (1.20, 1.37)4.09 × 10-14*46.241.65 (1.35, 2.02)1.38 × 10-6*
Esophageal cancer1130702,1161.67 (1.24, 2.25)6.84 × 10-4*22.684.78 (2.10, 10.90)1.97 × 10-4*
Gastric ulcer8651666,8791.54 (1.37, 1.72)3.83 × 10-14*44.961.95 (1.40, 2.71)7.31 × 10-5*
Duodenal ulcer5713666,8791.53 (1.34, 1.75)8.47 × 10-10*0.001.64 (1.07, 2.52)0.024
Acute gastritis3048643,4781.29 (1.09, 1.53)0.003*0.001.54 (0.91, 2.62)0.106
Chronic gastritis7975643,4781.33 (1.18, 1.49)1.55 × 10-6*77.041.33 (0.96, 1.86)0.091
Gastric cancer1608701,4721.42 (1.13, 1.79)0.003*0.002.29 (1.14, 4.59)0.020
Lower gastrointestinal diseasesIrritable bowel disease15,718641,4891.22 (1.12, 1.32)3.50 × 10-6*11.841.43 (1.10, 1.85)0.008*
Celiac disease4808631,7000.82 (0.66, 1.02)0.0710.000.87 (0.53, 1.43)0.590
Diverticular disease50,065587,9691.25 (1.18, 1.33)5.23 × 10-14*67.291.56 (1.30, 1.87)1.41 × 10-6*
Crohn’s disease10,846645,7181.25 (1.11, 1.40)3.03 × 10-4*0.001.48 (1.01, 2.16)0.042
Ulcerative colitis16,770651,2551.15 (1.04, 1.26)0.004*0.000.94 (0.71, 1.25)0.677
Colorectal cancer9519686,9531.03 (0.92, 1.14)0.63229.941.03 (0.76, 1.39)0.841
Hepatobiliary and pancreatic diseasesNon-alcoholic fatty liver disease3242707,6311.49 (1.26, 1.76)3.82 × 10-6*0.002.11 (1.15, 3.88)0.016*
Alcoholic liver disease2955680,3691.99 (1.65, 2.41)1.49 × 10-12*92.682.26 (1.26, 4.03)0.006
Cirrhosis5904706,2001.68 (1.40, 2.02)3.39 × 10-8*0.001.92 (1.06, 3.47)0.032
Liver cancer714702,0081.57 (1.13, 2.17)0.007*0.001.96 (0.73, 5.25)0.183
Cholangitis1708664,7491.02 (0.80, 1.29)0.8920.001.31 (0.61, 2.84)0.489
Cholecystitis5893664,7491.47 (1.29, 1.68)4.71 × 10-9*84.722.38 (1.57, 3.60)4.14 × 10-5*
Cholelithiasis42,510664,7491.20 (1.13, 1.27)5.75 × 10-9*0.001.33 (1.02, 1.73)0.035
Acute pancreatitis6634679,7131.39 (1.23, 1.56)6.71 × 10–8*79.711.55 (1.04, 2.31)0.031
Chronic pancreatitis3173679,7131.38 (1.17, 1.64)1.79 × 10–4*0.001.27 (0.74, 2.16)0.384
Pancreatic cancer1643701,4721.00 (0.79, 1.26)0.99967.212.08 (1.06, 4.10)0.034
OtherAcute appendicitis25,361690,1491.15 (1.08, 1.23)1.27 × 10–5*0.001.15 (0.92, 1.44)0.221
  1. *

    Significant association after multiple testing.

  2. UVMR, univariable Mendelian randomization; MVMR, multivariable Mendelian randomization; OR, odds ratio; CI, confidence interval. *Significant association after multiple testing.

Table 2
Associations of genetically predicted alcohol consumption with 24 gastrointestinal diseases in univariable and multivariable Mendelian randomization analyses.
DiseaseTotal casesTotal controlsUVMRMVMR adjusted for smoking initiation
OR (95% CI)p ValueI2 (95% CI)OR (95% CI)p Value
Upper gastrointestinal diseasesGastroesophageal reflux34,135634,6290.99 (0.81, 1.21)0.89346.240.88 (0.72, 1.08)0.219
Esophageal cancer1130702,1162.86 (1.18, 6.91)0.02022.681.28 (0.59, 2.82)0.533
Gastric ulcer8651666,8791.30 (0.95, 1.77)0.09844.961.06 (0.77, 1.47)0.721
Duodenal ulcer5713666,8791.92 (1.23, 3.00)0.004*0.001.54 (1.01, 2.34)0.045
Acute gastritis3048643,4780.99 (0.58, 1.69)0.9600.000.88 (0.52, 1.48)0.621
Chronic gastritis7975643,4781.33 (0.90, 1.95)0.14777.041.33 (0.93, 1.89)0.115
Gastric cancer1608701,4721.57 (0.75, 3.30)0.2330.001.59 (0.79, 3.21)0.194
Lower gastrointestinal diseasesIrritable bowel disease15,718641,4890.73 (0.57, 0.93)0.01211.840.74 (0.57, 0.97)0.027
Celiac disease4808631,7000.69 (0.44, 1.07)0.0970.001.04 (0.64, 1.68)0.887
Diverticular disease50,065587,9690.95 (0.79, 1.13)0.55367.290.94 (0.79, 1.13)0.527
Crohn’s disease10,846645,7180.91 (0.62, 1.32)0.6130.000.74 (0.53, 1.05)0.088
Ulcerative colitis16,770651,2551.11 (0.82, 1.50)0.5090.000.88 (0.67, 1.15)0.358
Colorectal cancer9519686,9531.09 (0.76, 1.55)0.64929.941.28 (0.95, 1.72)0.098
Hepatobiliary and pancreatic diseasesNon-alcoholic fatty liver disease3242707,6311.20 (0.63, 2.28)0.5740.000.99 (0.54, 1.79)0.962
Alcoholic liver disease2955680,36914.35 (7.69, 26.81)6.32 × 10-17*92.689.60 (5.28, 17.46)1.25 × 10-13*
Cirrhosis5904706,2002.96 (1.50, 5.85)0.002*0.002.41 (1.29, 4.52)0.006*
Liver cancer714702,0081.16 (0.43, 3.11)0.7750.000.76 (0.29, 2.02)0.585
Cholangitis1708664,7490.96 (0.44, 2.08)0.9120.000.72 (0.33, 1.55)0.397
Cholecystitis5893664,7491.36 (0.91, 2.03)0.13284.720.96 (0.64, 1.45)0.862
Cholelithiasis42,510664,7491.02 (0.75, 1.39)0.8780.001.03 (0.79, 1.35)0.801
Acute pancreatitis6634679,7131.36 (0.91, 2.03)0.12879.711.17 (0.78, 1.75)0.456
Chronic pancreatitis3173679,7132.96 (1.80, 4.89)2.13 × 10-5*0.003.24 (1.86, 5.64)3.18 × 10-5**
Pancreatic cancer1643701,4720.63 (0.32, 1.26)0.19367.210.79 (0.40, 1.56)0.496
OtherAcute appendicitis25,361690,1490.80 (0.63, 1.01)0.0630.000.77 (0.61, 0.97)0.024
  1. *

    Significant association after multiple testing.

  2. UVMR, univariable Mendelian randomization; MVMR, multivariable Mendelian randomization; OR, odds ratio; CI, confidence interval.

Additional files

MDAR checklist
https://cdn.elifesciences.org/articles/84051/elife-84051-mdarchecklist1-v2.pdf
Supplementary file 1

Supplementary material.

(A) Information of included studies and consortia. (B) Definition of gastrointestinal diseases in UK Biobank and FinnGen. (C) Single nucleotide polymorphisms used as instrumental variables for smoking and alcohol consumption. (D) Power estimation of this Mendelian randomization analysis. (E) False discovery rate adjusted p values for all tested association. (F) Association of genetically-predicted smoke initiation with gastrointestinal disease in univaribale mendelian randomization. (G) Association of genetically-predicted smoking initiation (excluding 23andMe and UK Biobank), alcohol consumption (excluding 23andMe and UK Biobank) and lifetime smoking index with gastrointestinal disease in univariable mendelian randomization. (H) Association of genetically-predicted smoke initiation and alcohol consumption with gastrointestinal disease in multivaribale mendelian randomization. (I) Association of genetically-predicted alcohol consumption with gastrointestinal disease in univariable mendelian randomization. (J) Association of genetically-predicted alcohol consumption instrumented by rs1229984 in ADH1B with gastrointestinal diseases. (K) Evidence of causal association of smoking and drinking with 24 gastrointestinal diseases in the current study. (L) Association of genetically-predicted smoking initiation (excluding 23andMe and UK Biobank) with 24 gastrointestinal diseases. (M) Associations of genetically-predicted lifetime smoking with 24 gastrointestinal diseases. (N) Association of genetically-predicted alcohol consumption (excluding 23andMe and UK Biobank) with 24 gastrointestinal diseases.

https://cdn.elifesciences.org/articles/84051/elife-84051-supp1-v2.xlsx
Reporting standard 1

STROBE-MR checklist for current Mendelian randomization study.

https://cdn.elifesciences.org/articles/84051/elife-84051-repstand1-v2.pdf

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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