Association between serum iron status and gout: results from the NHANES and Mendelian randomization study

Aims. Previous observational studies have provided inconsistent evidence for the association between serum iron status and the risk of gout. Moreover, it remains uncertain whether the observed association is causal or due to confounding or reverse causality. This research aimed to investigate the association of serum iron status indicators with the risk of gout and to further examine the causal relationship by the Mendelian randomization (MR) method. Methods. We first conducted a cross-sectional study from the National Health and Nutrition Examination Survey 2017-2018, including a total of 4635 participants. The association of serum iron status indicators with gout risk was evaluated using a multivariable logistic regression model. Furthermore, a two-sample MR study using genetic data from large-scale genome-wide association studies of serum iron status indicators (246 139 individuals) and gout (discovery: 13 179 cases and 75 0634 controls; replication: 5292 cases and 368 788 controls; 2115 cases and 67 259 controls) was conducted to infer causality. Inverse-variance-weighting (IVW) was applied as the main method of MR analysis. A series of sensitivity analyses were used to evaluate the robustness of their relationship. Results. In the cross-sectional study, there was no significant relationship between serum iron status indicators and gout risk. However, IVW results showed that genetically predicted serum iron and transferrin saturation (TSAT) were significantly associated with the increased risk of gout in the discovery analysis [odds ratio (OR): 1.21; 95% confidence interval (CI): 1.10-1.32; P = 9.80 × 10^-5 for serum iron and OR: 1.16; 95% CI: 1.08-1.25; P = 7.14 × 10^-5 for TSAT]. The replication analysis provided similar results compared with the discovery analysis. Conclusion. Our study provides support for potential causal associations between serum iron and the altered risk of gout. Further investigations are warranted to elucidate the biological processes through which iron influences susceptibility to gout.