Background/Purpose: Transferrin and its cell-surface receptor regulate iron uptake and ferritin sequesters free iron and acts as a store for excess iron. Ferritin has been positively associated with serum urate in the National Health and Nutrition Examination Survey III [1]. There have been observational and interventional studies suggesting a role for iron as a trigger for gout flares, which may be due to pro-inflammatory activities associated with iron [2]. Consistent with this, genetic variation in the transferrin receptor has been associated with gout and with an increased likelihood of self-report of an iron-rich food as a trigger of flares [3]. This observational study aimed to replicate the association of serum ferritin with serum urate (SU) and to test for association of serum ferritin with gout.

Methods: Association with gout was assessed in European (100 cases, 60 controls) and Polynesian (100 cases, 60 controls) male individuals from New Zealand (NZ) and a mixture of Latino, African American and European (33 cases, 60 controls) individuals from the United States (US). People with liver damage/ disease were excluded. For the SU association analysis, 180 participants without gout from NZ and the US and an additional 1,260 participants from the Jackson Heart Study (JHS) were used. Participants taking diuretic medication, or who had kidney disease or gout or first-degree relatives with gout were excluded from the SU analysis. Multiple regression analyses adjusted for age, sex (where relevant) and body mass index were done using R v3.3.0. Self-reported grandparental ancestry (for Polynesian) and C-reactive protein level (for JHS and US) were also included as covariates in the various analyses. Beta and OR statistics are expressed per 10 ng/mL increase in ferritin.

Results: Serum ferritin was positively associated with gout in NZ Polynesian [OR=1.031, P=4.4E-03] and US [OR=1.214, P=6.9E-05] participants but not NZ Europeans [OR=0.997, P=0.84] (Table). A positive association of ferritin with urate was observed in both NZ Polynesian [ß=0.081 µmol/L, P=1.1E-03] and US [ß=0.29 µmol/L, P=4.3E-06] individuals but not in NZ Europeans [ß=0.052 µmol/L, P=0.33]. A positive association of serum ferritin with SU was found in both males (ß=0.046 µmol/L, P=9.3E-03) and females (ß=0.081 µmol/L, P=1.6E-03) in the JHS.

Conclusion: The association of ferritin with SU and gout was independent of C-reactive protein level, suggesting that the relationship is not due to the elevation of ferritin in inflammation [4] and consistent with a direct role for iron metabolism in the control of SU and gout. This is supported by the previous report of association of the transferrin receptor with gout. 1. Ghio et al. Free Radic Res. 2005;39:337-42. 2. Facchini. Rheumatology. 2003;42:1550-55. 3. Merriman et al. Arthritis Rheumatol.2015;S67(10). 4. Kell et al. Metallomics, 2014. 6:748-73.