Causal associations of iron status with gout and rheumatoid arthritis, but not with inflammatory bowel disease

Abstract

Background & aims: We conducted a two-sample Mendelian randomization study to assess the associations of iron homeostasis with the risk of gout, rheumatoid arthritis and inflammatory bowel disease.

Methods: Single-nucleotide polymorphisms for iron status were selected at the genome-wide significance level from a large genome-wide association study of 48 972 European-descent individuals. Summary-level data for gout, rheumatoid arthritis and inflammatory bowel disease were obtained from The Global Urate Genetics Consortium and two large genome-wide association studies, respectively. Inverse-variance weighted method with random-effects and sensitivity analyses were performed.

Results: Genetic predisposition to high iron status was causally associated with higher odds of gout, lower odds of rheumatoid arthritis, but not associated with inflammatory bowel disease. The odds ratios of gout were 1.35 (95% confidence interval (CI), 1.00, 1.81; p = 0.047), 2.07 (95% CI, 1.23, 3.50; p = 0.006), 1.27 (95% CI, 1.07, 1.50; p = 0.007) and 0.69 (95% CI, 0.54, 0.90; p = 0.005) per one standard deviation increment of serum iron, ferritin, transferrin saturation, and transferrin levels, respectively. For rheumatoid arthritis, the corresponding odds ratios were 0.79 (95% CI, 0.65, 0.94; p = 0.010), 0.59 (95% CI, 0.40, 0.86; p = 0.007), 0.84 (95% CI, 0.75, 0.94; p = 0.003) and 1.28 (95% CI, 1.06, 1.55; p = 0.012).

Conclusions: Based on consistent findings for four iron biomarkers, genetically high iron status was positively associated with gout and inversely associated with rheumatoid arthritis. There was limited MR evidence supporting a causal association between iron status and inflammatory bowel disease.

Keywords: Gout; Inflammatory bowel disease; Iron status; Mendelian randomization; Rheumatoid arthritis.