Previous studies have convincingly shown that genetic variants in the genes HFE and TMPRSS6 are associated with the iron parameters serum iron, ferritin, transferrin saturation and total iron binding capacity. It was commonly thought that these associations could be explained by the intermediate effect of the genes on serum hepcidin, the central regulatory molecule of systemic iron homeostasis. However, a study in an isolated Italian population could not completely confirm this. Our results do also not support an intermediate role for hepcidin in these associations. This suggests that there might be other, yet unknown, serum hepcidin-independent mechanisms which play a role in the associations of HFE and TMPRSS6 genetic variants with serum iron parameters. (By Miss Tessel Galesloot, http://jmg.bmj.com/content/early/2013/06/20/jmedgenet-2013-101673 )