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Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma: a mediation Mendelian randomization study

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This study aims to investigate the causal relationships between specific dietary habits and the risk of gout, while identifying the mediators involved in these associations.


We initially assessed the causal effects of five dietary habits on gout by two-sample Mendelian randomization (MR). Subsequently, we identified mediators from five plasma metabolites by two-step MR, including urate, urea, sex hormone-binding globulin (SHBG), interleukin-18 (IL-18), and C-reactive protein (CRP). Next, we quantified the proportion of mediation effects by multivariable Mendelian randomization (MVMR). Last, we performed reverse MR analyses. Sensitivity analyses were conducted to enhance the robustness of our findings.


Only coffee intake demonstrated a significant negative casual effect on gout (inverse variance weighted: OR = 0.444, p = 0.049). In two-step MR, coffee intake decreased urate and urea while increased SHBG levels, but did not affect IL-18 and CRP levels. Besides, urate and urea showed positive causal effects while SHBG exhibited a negative impact on gout. In mediation analysis, urate, urea, and SHBG respectively mediated 53.60%, 16.43%, and 4.81% of the total causal effect of coffee intake on gout. The three mediators collectively mediated 27.45% of the total effect. Reverse MR analyses suggested no significant reverse causal effects. Sensitivity analyses supported the reliability of our causal inferences.


Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma. These findings accentuate the benefits of coffee intake for gout management. The mediators may provide a novel insight into potential therapeutic targets for gout prevention.

Key Points

• This study determines the causally protective effect of coffee intake on gout.

• We reveal that coffee intake reduced the risk of gout by decreasing urate and urea while increasing SHBG levels in plasma.

• Identifying specific mediators in the causal pathway from coffee intake to gout provides valuable information for clinical interventions of gout.

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Data availability

The GWAS data are available in the IEU open GWAS Project (


  1. Kannuthurai V, Gaffo A (2023) Management of patients with gout and kidney disease: a review of available therapies and common missteps. Kidney 4(9):e1332–e40.

    Article  Google Scholar 

  2. Louie PK, Kumar R, Ruhoy S, Nemani VM (2023) Gout-induced cervical deformity and progressive myelopathy mimicking infection requiring cervical reconstruction. World Neurosurg.

    Article  PubMed  Google Scholar 

  3. Chen DD, Li Q, Wu JC (2023) Efficient removal of purine compounds from solutions via biomass carbons derived from pomelo peel. J Biosci Bioeng 136(5):383–390.

    Article  CAS  PubMed  Google Scholar 

  4. Hao G, Xu X, Song J, Zhang J, Xu K (2023) Lipidomics analysis facilitate insight into the molecular mechanisms of urate nephropathy in a gout model induced by combination of MSU crystals injection and high-fat diet feeding. Front Mol Biosci 10:1190683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yuan S, Wang L, Sun J, Yu L, Zhou X, Yang J et al (2022) Genetically predicted sex hormone levels and health outcomes: phenome-wide Mendelian randomization investigation. Int J Epidemiol 51(6):1931–1942.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kim SK (2022) The mechanism of the NLRP3 inflammasome activation and pathogenic implication in the pathogenesis of gout. J Rheum Dis 29(3):140–153.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pogue AI, Jaber V, Zhao Y, Lukiw WJ (2017) Systemic inflammation in C57BL/6J mice receiving dietary aluminum sulfate; up-regulation of the pro-inflammatory cytokines IL-6 and TNFα, C-reactive protein (CRP) and miRNA-146a in blood serum. J Alzheimers Dis Parkinsonism 7(6).

  8. Choi SH, Song HS, Hwang J (2023) Herbal medicine for external use in acute gouty arthritis: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 102(37):e34936.

    Article  PubMed  Google Scholar 

  9. Guo Y, Zhou F, Xu H (2023) Gout and risk of venous thromboembolism: a systematic review and meta-analysis of cohort studies. Int J Rheum Dis 26(2):344–353.

    Article  PubMed  Google Scholar 

  10. Xie Y, Li Y, Zhang J, Chen Y, Ren R, Xiao L et al.  (2023) Assessing the causal association between human blood metabolites and the risk of gout. Eur J Clin Invest e14129.

  11. Xu L, Borges MC, Hemani G, Lawlor DA (2017) The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study. Diabetologia 60(11):2210–2220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guo H, Wang S, Peng H, Wang M, Li L, Huang J et al (2023) Dose-response relationships of tea and coffee consumption with gout: a prospective cohort study in the UK Biobank. Rheumatology (Oxford) 62(9):3043–3050.

    Article  PubMed  Google Scholar 

  13. Dai H, Hou T, Wang Q, Zhu Z, Zhu Y, Zhao Z et al (2023) The effect of metformin on urate metabolism: findings from observational and Mendelian randomization analyses. Diabetes Obes Metab.

    Article  PubMed  Google Scholar 

  14. Clebak KT, Morrison A, Croad JR (2020) Gout: rapid evidence review. Am Fam Physician 102(9):533–538

    PubMed  Google Scholar 

  15. Jung JH, Seok H, Choi SJ, Kim C, Bang CH, Song GG (2020) Relationship between coffee consumption and serum uric acid level in the general Korean population: a nationwide cross-sectional study. Int J Rheum Dis 23(3):420–427.

    Article  CAS  PubMed  Google Scholar 

  16. Shirai Y, Nakayama A, Kawamura Y, Toyoda Y, Nakatochi M, Shimizu S et al (2022) Coffee consumption reduces gout risk independently of serum uric acid levels: Mendelian randomization analyses across ancestry populations. ACR Open Rheumatol 4(6):534–539.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang X, Zi XY, Hao C (2022) New insight in the immune mechanisms in hyperuricemia after renal transplantation: a narrative review. Eur Rev Med Pharmacol Sci 26(14):4969–78.

    Article  CAS  PubMed  Google Scholar 

  18. Xi S, Shao Zhiguo, Li L, Gui Z, Liu P, Jiang Q et al (2022) Tongbixiao pills improve gout by reducing uric acid levels and inhibiting inflammation. Dose Response 20(2):15593258221090340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Simó R, Sáez-López C, Barbosa-Desongles A, Hernández C, Selva DM (2015) Novel insights in SHBG regulation and clinical implications. Trends Endocrinol Metab 26(7):376–383.

    Article  CAS  PubMed  Google Scholar 

  20. Bourebaba N, Ngo T, Śmieszek A, Bourebaba L, Marycz K (2022) Sex hormone binding globulin as a potential drug candidate for liver-related metabolic disorders treatment. Biomed Pharmacother 153:113261.

    Article  CAS  PubMed  Google Scholar 

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We thank the IEU open GWAS for providing summary statistics data.


This study is supported by the National Natural Science Foundation of China (82273094) and the Hubei Key Laboratory Opening Project (2021KFY064).

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Tingting Qin drafted the manuscript, Yuxin Chu prepared the figures, Yi Yao contributed to the acquisition of data, Cai Zhang and Bin Xu performed the analysis, and Qibin Song contributed to the conception and design of the study.

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Correspondence to Qibin Song.

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Qin, T., Chu, Y., Yao, Y. et al. Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma: a mediation Mendelian randomization study. Clin Rheumatol 43, 1735–1743 (2024).

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