Genetically Predicted Iron Status Is a Causal Risk of Rheumatoid Arthritis: A Mendelian Randomization Study

Abstract

Background Current knowledge on iron's role in rheumatoid arthritis (RA) development is very limited, with studies yielding inconsistent findings. We conducted a two-sample Mendelian randomization study to assess the associations of iron status with the risk of RA.

Methods This study leveraged genetic data from a large genome-wide association study (GWAS) of 257,953 individuals to identify single nucleotide polymorphisms (SNPs) associated with iron status. We then analyzed these data in conjunction with summary-level data on RA from the IEU open GWAS project, which included 5,427 RA cases and 479,171 controls. An inverse-variance weighted method with random effects was employed, along with sensitivity analyses, to assess the relationship between iron status and RA risk.

Results Genetic predisposition to high ferritin and serum iron status was causally associated with lower odds of RA. Ferritin had an odds ratio (OR) of 0.997 (95% confidence interval [CI]: 0.995–0.997; p = 0.010), indicating that a one-unit increase in ferritin is associated with a 0.3% decrease in the odds of RA. Similarly, serum iron had an OR of 0.997 (95% CI: 0.995–0.999; p = 0.014). However, MR analyses found no significant causal associations between total iron-binding capacity (OR = 1.0, 95% CI: 0.999–1.002; p = 0.592) or transferrin saturation percentage (OR = 0.998, 95% CI: 0.996–1.000; p = 0.080) and risk of developing RA.

Conclusions This study suggests that individuals with genes linked to higher iron levels may have a lower risk of developing RA. Our findings indicate that the total amount of iron in the body, rather than how it is distributed, might be more important for RA. This raises the intriguing possibility that iron supplementation could be a preventative strategy, but further research is necessary.

Keywords

iron - ferritin - rheumatoid arthritis - Mendelian randomization - single nucleotide polymorphism

Disclosure Statement

No potential conflict of interest was reported by the author.

Data Availability Statement

This study analyzed publicly available datasets that can be accessed via NTNU Open Research Data (https://doi.org/10.18710/S9TJEL) and the IEU OpenGWAS database (https://gwas.mrcieu.ac.uk/).

Publication History

Article published online:
29 August 2024

• References

• 1 Benito-Garcia E, Feskanich D, Hu FB, Mandl LA, Karlson EW. Protein, iron, and meat consumption and risk for rheumatoid arthritis: a prospective cohort study. Arthritis Res Ther 2007; 9 (01) R16
• 2 Gu P, Pu B, Liu T. et al. Appraising causal risk and protective factors for rheumatoid arthritis. Bone Joint Res 2023; 12 (09) 601-614
• 3 Cronin SJF, Woolf CJ, Weiss G, Penninger JM. The role of iron regulation in immunometabolism and immune-related disease. Front Mol Biosci 2019; 6: 116
• 4 Katsarou A, Pantopoulos K. Basics and principles of cellular and systemic iron homeostasis. Mol Aspects Med 2020; 75: 100866
• 5 Lawen A, Lane DJ. Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action. Antioxid Redox Signal 2013; 18 (18) 2473-2507
• 6 Nairz M, Weiss G. Iron in infection and immunity. Mol Aspects Med 2020; 75: 100864
• 7 Wang Z, Yin W, Zhu L. et al. Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production. Immunity 2018; 49 (01) 80-92.e7
• 8 Jiang Y, Li C, Wu Q. et al. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses. Nat Commun 2019; 10 (01) 2935
• 9 Wang H, Zhang R, Shen J. et al. Circulating level of blood iron and copper associated with inflammation and disease activity of rheumatoid arthritis. Biol Trace Elem Res 2023; 201 (01) 90-97
• 10 Yang M, Su Y, Xu K. et al. Iron, copper, zinc and magnesium on rheumatoid arthritis: a two-sample Mendelian randomization study. Int J Environ Health Res 2024; 34 (07) 2776-2789
• 11 Yuan S, Larsson S. Causal associations of iron status with gout and rheumatoid arthritis, but not with inflammatory bowel disease. Clin Nutr 2020; 39 (10) 3119-3124
• 12 Zhou J, Liu C, Sun Y. et al. Genetically predicted circulating levels of copper and zinc are associated with osteoarthritis but not with rheumatoid arthritis. Osteoarthritis Cartilage 2021; 29 (07) 1029-1035
• 13 Dönertaş HM, Fabian DK, Valenzuela MF, Partridge L, Thornton JM. Common genetic associations between age-related diseases. Nat Aging 2021; 1 (04) 400-412
• 14 Moksnes MR, Graham SE, Wu KH. et al. Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT. Commun Biol 2022; 5 (01) 591
• 15 Cronin SJF, Seehus C, Weidinger A. et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 2018; 563 (7732): 564-568
• 16 Gao X, Song Y, Wu J. et al. Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus. J Clin Invest 2022; 132 (09) e152345
• 17 Han C, Rahman MU, Doyle MK. et al. Association of anemia and physical disability among patients with rheumatoid arthritis. J Rheumatol 2007; 34 (11) 2177-2182
• 18 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352 (10) 1011-1023
• 19 Tański W, Chabowski M, Jankowska-Polańska B, Jankowska EA. Iron metabolism in patients with rheumatoid arthritis. Eur Rev Med Pharmacol Sci 2021; 25 (12) 4325-4335