Is type 2 diabetes mellitus an inverse risk factor for the development of rheumatoid arthritis?

Abstract

Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both chronic diseases. Although the link between metabolic abnormalities and dysregulated inflammation has received much attention, it is not known whether T2DM can be a risk for the development of RA. Also, observational studies have the disadvantage that the possibility of confounding factors, such as environmental factors, cannot be ruled out. Therefore, the current study performed the mendelian randomization (MR) analysis using recent large-scale genome-wide association studies datasets of T2DM and RA separately European and Asian ancestries. As a result, T2DM had an inverse causal effect on the risk of RA. This study proposed a novel hypothesis that a protective effect of T2DM for the risk of RA.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365:1333.

    CAS  Article  Google Scholar 

  2. 2.

    Solomon DH, Love TJ, Canning C, Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis. Ann Rheum Dis. 2010;69:2114–7.

    Article  Google Scholar 

  3. 3.

    Dubreuil M, Rho YH, Man A, Zhu Y, Zhang Y, Thorvardur JL, et al. Diabetes incidence in psoriatic arthritis, psoriasis and rheumatoid arthritis: a UK population-based cohort study. Rheumatology. 2014;53:346–52.

    CAS  Article  Google Scholar 

  4. 4.

    Lu MC, Yan ST, Yin WY, Koo M, Lai NS. Risk of rheumatoid arthritis in patients with type 2 diabetes: a nationwide population-based case-control study. PLoS One. 2014;9:e101528.

    Article  Google Scholar 

  5. 5.

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

    Article  Google Scholar 

  6. 6.

    Spracklen CN, Horikoshi M, Kim YJ, Lin K, Bragg F, Moon S, et al. Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature. 2020;582:240–5.

    CAS  Article  Google Scholar 

  7. 7.

    Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018;50:1505–13.

    CAS  Article  Google Scholar 

  8. 8.

    Okada Y, Wu D, Trynka G, Terao C, Ikari K, Kochi Y, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014;506:376–81.

    CAS  Article  Google Scholar 

  9. 9.

    Zhu Z, Zheng Z, Zhang F, Wu Y, Trzaskowski M, Maier R, et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat Commun. 2018;9:224.

    Article  Google Scholar 

  10. 10.

    John B, David A. J, Regina M. B. Problems with instrumental variables estimation when the correlation between the instruments and the endogenous explanatory variable is weak. J Am Stat Assoc. 1995;90:443–50.

    Google Scholar 

  11. 11.

    Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. arXiv. https://arxiv.org/abs/1801.09652.

  12. 12.

    Ogawa K, Stuart PE, Tsoi LC, Suzuki K, Nair RP, Mochizuki H, et al. A transethnic mendelian randomization study identifies causality of obesity on risk of psoriasis. J Invest Dermatol. 2019;139:1397–400.

    CAS  Article  Google Scholar 

  13. 13.

    Burgess S, Smith GD, Davies NM, Dudbridge F, Gill D, Glymour MM, et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 2019;4:186.

    Article  Google Scholar 

  14. 14.

    Carey IM, Critchley JA, DeWilde S, Harris T, Hosking FJ, Cook DG. Risk of infection in type 1 and type 2 diabetes compared with the general population: a matched cohort study. Diabetes Care. 2018;41:513–21.

    Article  Google Scholar 

  15. 15.

    Turina M, Fry DE, Polk HC Jr. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med. 2005;33:1624–33.

    Article  Google Scholar 

  16. 16.

    Boldizsar F, Berki T, Miseta A, Németh P. Effect of hyperglycemia on the basal cytosolic free calcium level, calcium signal and tyrosine-phosphorylation in human T-cells. Immunol Lett. 2002;82:159–64.

    CAS  Article  Google Scholar 

  17. 17.

    Müller-Graff FT, Fitzner B, Jaster R, Vollmar B, Zechner D. Impact of hyperglycemia on autoimmune pancreatitis and regulatory T-cells. World J Gastroenterol. 2018;24:3120–9.

    Article  Google Scholar 

  18. 18.

    Dries DL. Genetic ancestry, population admixture, and the genetic epidemiology of complex disease. Circ Cardiovasc Genet. 2009;2:540–3.

    Article  Google Scholar 

  19. 19.

    Gurdasani D, Barroso I, Zeggini E, Sandhu MS. Genomics of disease risk in globally diverse populations. Nat Rev Genet. 2019;20:520–35.

    CAS  Article  Google Scholar 

  20. 20.

    Ntuk UE, Gill JM, Mackay DF, Sattar N, Pell JP. Ethnic-specific obesity cutoffs for diabetes risk: cross-sectional study of 490,288 UK biobank participants. Diabetes Care. 2014;37:2500–7.

    Article  Google Scholar 

  21. 21.

    Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36:1789–96.

    CAS  Article  Google Scholar 

  22. 22.

    Gkatzionis A, Burgess S. Contextualizing selection bias in Mendelian randomization: how bad is it likely to be? Int J Epidemiol. 2019;48:691–701.

    Article  Google Scholar 

  23. 23.

    Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA. Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol. 2006;163:397–403.

    Article  Google Scholar 

Download references

Acknowledgements

Genetic datasets were obtained from Wellcome Trust Case Control. Consortium; Meta-Analyses of Glucose and Insulin-related traits Consortium. Investigators; Genetic Investigation of Anthropometric Traits Consortium; Asian Genetic Epidemiology Network–Type 2 Diabetes Consortium; South Asian Type 2 Diabetes Consortium (Morris et al. Nat Genet. 2012;44:981–90.) and work done by Okada et al. [8]. I thank all investigators for sharing the data.

Author information

Affiliations

Authors

Contributions

Conceptualization, formal analysis, and writing: JI. Writing review and editing: YK and TT.

Corresponding author

Correspondence to Jun Inamo.

Ethics declarations

Conflict of interest

TT has received research grants from Astellas Pharma Inc, Bristol-Myers KK, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd, Takeda Pharmaceutical Co. Ltd, Teijin Pharma Ltd, AbbVie GK, Asahi Kasei Pharma Corp, Mitsubishi Tanabe Pharma Co, Pfizer Japan Inc, and Taisho Toyama Pharmaceutical Co. Ltd, Eisai Co. Ltd, AYUMI Pharmaceutical Corporation, and Nipponkayaku Co. Ltd, and speaking fees from AbbVie GK, Bristol-Myers KK, Chugai Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Co, Pfizer Japan Inc, and Astellas Pharma Inc, and Daiichi Sankyo Co. Ltd, and consultant fees from Astra Zeneca KK, Eli Lilly Japan KK, Novartis Pharma KK, Mitsubishi Tanabe Pharma Co, Abbivie GK, Nipponkayaku Co. Ltd, Janssen Pharmaceutical KK, Astellas Pharma Inc, and Taiho Pharmaceutical Co. Ltd. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Inamo, J., Kochi, Y. & Takeuchi, T. Is type 2 diabetes mellitus an inverse risk factor for the development of rheumatoid arthritis?. J Hum Genet (2020). https://doi.org/10.1038/s10038-020-00837-2

Download citation

Search