Alcohol intake and risk of rheumatoid arthritis: a Mendelian randomization study

Alkoholkonsum und Risiko der rheumatoiden Arthritis: eine Mendel-Randomisierungsstudie



To examine whether alcohol intake is causally associated with rheumatoid arthritis (RA).


We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and a GWAS meta-analysis of 5539 autoantibody-positive RA patients and 20,169 controls as the outcome.


We selected 24 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables (IVs) to improve inference, 16 of which were inversely associated with RA. The IVW method showed no evidence of a causal association between alcohol intake and RA (beta = 0.218, SE = 0.213, p = 0.306). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.027, p = 0.292). The MR-Egger analysis and the weighted median approach showed no causal association between alcohol intake and RA (beta = −0.778, SE = 0.947, p = 0.420 and beta = −0.286, SE = 0.302, p = 0.344, respectively). Cochran’s Q test did not indicate heterogeneity between IV estimates based on the individual variants, and results from a “leave-one-out” analysis demonstrated that no single SNP was driving the IVW point estimate.


The MR analysis does not support a causal inverse association between alcohol intake and RA occurrence.



In der vorliegenden Studie wurde untersucht, ob Alkoholkonsum kausal mit der rheumatoiden Arthritis (RA) zusammenhängt.


Es wurde eine Zwei-Stichproben-Mendel-Randomisierungs(MR)-Analyse mit Inverse-Varianz-Gewichtung (IVG), gewichtetem Median und MR-Egger-Regression durchgeführt. Dafür herangezogen wurden die öffentlich zugänglichen statistischen Kennzahlen zur Häufigkeit des Alkoholkonsums aus den genomweiten Assoziationsstudien (GWAS) der UK Biobank (n = 336.965) für die Exposition sowie eine GWAS-Metaanalyse von 5539 Autoantikörper-positiven Patienten mit RA und 20.169 Kontrollpersonen für das Outcome.


Insgesamt 24 Einzelnukleotidpolymorphismen (SNP), die mit genomweiter Signifikanz mit der Häufigkeit des Alkoholkonsums assoziiert waren, wurden als Instrumentvariablen (IV) ausgewählt, um bessere Schlussfolgerungen zu ermöglichen. Von diesen waren 16 invers mit RA assoziiert. Die IVG-Methode ergab keinen Hinweis auf einen kausalen Zusammenhang zwischen Alkoholkonsum und RA (beta = 0,218, SE = 0,213, p = 0,306). Die MR-Egger-Regression zeigte, dass eine Verzerrung des Ergebnisses durch eine gerichtete Pleiotropie unwahrscheinlich war (Achsenabschnitt =0,027, p = 0,292). Die MR-Egger-Analyse und der Ansatz mit gewichtetem Median ergaben keinen kausalen Zusammenhang zwischen Alkoholkonsum und RA (beta = −0,778, SE = 0,947, p = 0,420 bzw. beta = −0,286, SE = 0,302, p = 0,344). Der Cochran-Q-Test wies nicht auf eine Heterogenität zwischen IV-Schätzungen auf Grundlage der individuellen Varianten hin, und eine Leave-one-out-Analyse zeigte, dass nicht ein einzelner SNP die IVG-Punktschätzung bestimmte.


Die MR-Analyse stützt eine kausale inverse Assoziation zwischen Alkoholkonsum und dem Auftreten einer RA nicht.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44(2):512–525

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Bowden J, Davey Smith G, Haycock PC et al (2016) Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol 40(4):304–314

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Bowden J, Del Greco F, Minelli C et al (2016) Assessing the suitability of summary data for Mendelian randomization analyses using MR-Egger regression: the role of the I^ 2 statistic. Int J Epidemiol 45(6):1961–1974

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Brion M-JA, Shakhbazov K, Visscher PM (2012) Calculating statistical power in Mendelian randomization studies. International journal of epidemiology 42(5):1497–1501

    PubMed Central  Article  Google Scholar 

  5. 5.

    Burgess S, Butterworth A, Thompson SG (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 37(7):658–665

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Burgess S, Daniel RM, Butterworth AS et al (2014) Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol 44(2):484–495

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Burgess S, Dudbridge F, Thompson SG (2016) Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods. Stat Med 35(11):1880–1906

    PubMed  Article  Google Scholar 

  8. 8.

    Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32(5):377–389

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Edwards C, Cooper C (2006) Early environmental factors and rheumatoid arthritis. Clinical & Experimental. Immunology 143(1):1–5

    CAS  Google Scholar 

  10. 10.

    Egger M, Smith GD, Phillips AN (1997) Meta-analysis: principles and procedures. BMJ 315(7121):1533–1537

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Hartwig FP, Davies NM, Hemani G et al (2016) Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int J Epidemiol 45(6):1717–1726

    PubMed  Article  Google Scholar 

  12. 12.

    Hemani G, Zheng J (2016) Wade K et al MR-Base: a platform for systematic causal inference across the phenome using billions of genetic associations. bioRxiv. Acta Neurochir (Wien) 16:78972 (Dec)

    Google Scholar 

  13. 13.

    Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558

    PubMed  Article  Google Scholar 

  14. 14.

    Cochran WG, Rubin DB (1973) Controlling bias in observational studies: A review. Sankhyā: Indian J Stat Series A:417–446

    Google Scholar 

  15. 15.

    Jin Z, Xiang C, Cai Q et al (2014) Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies. Ann Rheum Dis 73(11):1962–1967

    PubMed  Article  Google Scholar 

  16. 16.

    Jonsson M, Verdrengh M, Brisslert M et al (2007) Ethanol prevents development of destructive arthritis. Proc Natl Acad Sci 104(1):258–263

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Lawlor DA (2016) Commentary: Two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol 45(3):908

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Lee YH, Bae S‑C, Choi SJ et al (2012) Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis. Mol Biol Rep 39(12):10627–10635

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Lee YH, Bae SC, Song GG (2013) Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occultcarriers) undergoing antitumor necrosis factor therapy. Clin Exp Rheumatol 31(1):118–121

    PubMed  Google Scholar 

  20. 20.

    Mandrekar P, Jeliazkova V, Catalano D et al (2007) Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IκB kinase activity and p65 phosphorylation in human monocytes. J Immunol 178(12):7686–7693

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Pierce BL, Burgess S (2013) Efficient design for Mendelian randomization studies: subsample and 2‑sample instrumental variable estimators. Am J Epidemiol 178(7):1177–1184

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Scott IC, Tan R, Stahl D et al (2013) The protective effect of alcohol on developing rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology 52(5):856–867

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Smith GD, Ebrahim S (2003) ‘Mendelian randomization’: Can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiolog 32(1):1–22

    Article  Google Scholar 

  24. 24.

    Smith GD, Ebrahim S (2004) Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33(1):30–42

    PubMed  Article  Google Scholar 

  25. 25.

    Stahl EA, Raychaudhuri S, Remmers EF et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Swerdlow DI, Kuchenbaecker KB, Shah S et al (2016) Selecting instruments for Mendelian randomization in the wake of genome-wide association studies. Int J Epidemiol 45(5):1600–1616

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Thompson JR, Minelli C, Bowden J et al (2017) Mendelian randomization incorporating uncertainty about pleiotropy. Stat Med 36(29):4627–4645

    PubMed  Article  Google Scholar 

  28. 28.

    Waldschmidt TJ, Cook RT, Kovacs EJ (2008) Alcohol and inflammation and immune responses: summary of the 2006 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 42(2):137–142

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references


This study was supported in part by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI15C2958).

Author information



Corresponding author

Correspondence to Y. H. Lee MD, PhD.

Ethics declarations

Conflict of interest

S.-C. Bae and Y. H. Lee declare that they have no competing interests.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Additional information


U. Müller-Ladner, Bad Nauheim

U. Lange, Bad Nauheim

Caption Electronic Supplementary Material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bae, S., Lee, Y.H. Alcohol intake and risk of rheumatoid arthritis: a Mendelian randomization study. Z Rheumatol 78, 791–796 (2019).

Download citation


  • Alcohol intake
  • Rheumatoid arthritis
  • Mendelian randomization
  • Genetic predisposition to disease
  • Genome-wide association study


  • Alkoholkonsum
  • Rheumatoide Arthritis
  • Mendel-Randomisierung
  • Genetische Krankheitsdisposition
  • Genomweite Assoziationsstudie