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Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations
  1. Michela Traglia1,
  2. Domenico Girelli2,
  3. Ginevra Biino3,4,
  4. Natascia Campostrini2,
  5. Michela Corbella2,
  6. Cinzia Sala1,
  7. Corrado Masciullo1,
  8. Fiammetta Viganò1,
  9. Iwan Buetti1,
  10. Giorgio Pistis1,
  11. Massimiliano Cocca1,
  12. Clara Camaschella1,5,
  13. Daniela Toniolo1,3
  1. 1Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano, Italy
  2. 2Department of Medicine, University of Verona, Verona, Italy
  3. 3Institute of Molecular Genetics, CNR, Pavia, Italy
  4. 4Institute of Population Genetics, CNR, Sassari, Italy
  5. 5Vita Salute University, San Raffaele Scientific Institute, Milano, Italy
  1. Correspondence to Daniela Toniolo, Division of Genetics and Cell Biology, San Raffaele Research Institute, Via Olgettina 58, Milano 20132, Italy; daniela.toniolo{at}


Background Hepcidin is the main regulator of iron homeostasis: inappropriate production of hepcidin results in iron overload or iron deficiency and anaemia.

Aims To study variation of serum hepcidin concentration in a normal population.

Results Hepcidin showed age and sex dependent variations that correlated with ferritin but not with serum iron and transferrin saturation. The size of the study population was underpowered to find genome wide significant associations with hepcidin concentrations but it allowed to show that association with serum iron, transferrin saturation and erythrocyte traits of common DNA variants in HFE (rs1800562) and TMPRSS6 (rs855791) genes is not exclusively dependent on hepcidin values. When multiple interactions between environmental factors, the iron parameters and hepcidin were taken into account, the HFE variant, and to lesser extent the TMPRSS6 variant, were associated with ferritin and with hepcidin normalised to ferritin (the hepcidin/ferritin ratio).

Conclusions The results suggest a mutual control of serum hepcidin and ferritin concentrations, a mechanism relevant to the pathophysiology of HFE haemochromatosis, and demonstrate that the HFE rs1800562 C282Y variant exerts a direct pleiotropic effect on the iron parameters, in part independent of hepcidin.

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  • Funding This work was funded by grants from: Compagnia San Paolo Torino, and Progetto Finalizzato Sanità RF-FSR-2007-647201 to DT, Telethon Foundation Onlus, Rome, Grant GGP080892008, Regione Lombardia Sal-11, ID 17389 and EU Contract LSHM-CT-2006-037296 EURIRON to CC.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval San Raffaele Hospital Ethical Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.