Associations of Iron Metabolism and Inflammation with All-Cause and Cardiovascular Mortality in a Large NHANES Community Sample: Moderating and Mediating Effects

Background and Aims This study aimed to assess the associations between serum iron concentration, C-reactive protein (CRP) concentration and the risk of all-cause mortality and cardiovascular mortality in the general population and to explore potential mediating and moderating effects. Methods and Results This study analyzed data from the National Health and Nutrition Examination Survey spanning the years 1999 to 2010, encompassing 23634 participants. Cox proportional hazards regression models were employed to investigate the independent associations of serum iron and CRP with all-cause and cardiovascular mortality. Moderation and mediation analyses explored the moderating effect of CRP on the association between the serum iron concentration and all-cause and cardiovascular mortality, and the mediating role of the serum iron concentration in the association between the CRP concentration and all-cause and cardiovascular mortality. After multivariate adjustments in the Cox model, serum iron and CRP levels were independently correlated with both all-cause and cardiovascular mortality risk. Moderation analyses revealed a more pronounced correlation between the serum iron concentration and both all-cause and cardiovascular mortality in participants with higher CRP levels. Mediation analysis indicated that the serum iron concentration partly mediated the impact of CRP on the risk of all-cause mortality (13.79%) and cardiovascular mortality (24.12%). Conclusion Serum iron and CRP are independently associated with all-cause and cardiovascular mortality. Moreover, the associations between serum iron concentrations and both all-cause and cardiovascular mortality are more pronounced in individuals with elevated CRP. Serum iron partially mediates the effect of CRP on all-cause and cardiovascular mortality.