Serum Hepcidin levels and association studies of TMPRSS6 and HFE variants provide further insights into regulation of iron homeostasis

Genetic variants of hepcidin-regulatory genes, TMPRSS6 and HFE, affect erythrocyte traits and iron parameters, namely serum iron and transferrin saturation in normal populations. To analyze whether this effect is mediated by the iron regulator hepcidin, we measured serum hepcidin levels in 1657 genotyped individuals from an Italian cohort, the Val Borbera (VB) population. Hepcidin levels showed age and sex dependent variations that correlated with ferritin but not with serum iron or transferrin saturation. We replicated the observation that common variants of the HFE (rs1800562, C282Y) and TMPRSS6 (rs855791,V736A) genes are associated with serum iron and transferrin saturation, but no association was found with hepcidin. Both variants showed a modest effect on the hepcidin/ferritin ratio, and the association was enhanced once iron-deficient and inflammationpositive samples were excluded from the analysis. Interestingly, in such a subset of samples, HFE C282Y was associated to ferritin at genome wide significance and the association was further enhanced after adjusting for hepcidin levels. Our results suggest that the main effect of HFE C282Y variant is to increase cell iron uptake through increased transferrin saturation. The effect is in part counterbalanced by impaired hepcidin levels which favor cell iron release, especially from macrophages, in this way likely reducing, serum ferritin levels. Finally we show that the effect of HFE and TMPRSS6 variants on erythroid traits is mainly mediated by variations of iron parameters, but not by variations of hepcidin.