Associations of common variants in HFE and TMPRSS6 with iron parameters are independent of serum hepcidin in a general population: a replication study

J Med Genet. 2013 Sep;50(9):593-8. doi: 10.1136/jmedgenet-2013-101673. Epub 2013 Jun 21.


Background: Genome-wide association studies have convincingly shown that single nucleotide polymorphisms (SNPs) in HFE and TMPRSS6 are associated with iron parameters. It was commonly thought that these associations could be explained by the intermediate effect on hepcidin concentration. A recent study in an isolated Italian population, however, concluded that these associations were not exclusively dependent on hepcidin values. We report here the second study to investigate the role of hepcidin in the associations between common variants in HFE and TMPRSS6 with iron parameters.

Methods: We extracted 101 SNPs in HFE and TMPRSS6 from genome-wide imputed SNP data of 1832 individuals from the general population (Nijmegen Biomedical Study). Single locus and haplotype associations with serum iron parameters and hepcidin were studied using linear regression analyses.

Results: We found that HFE rs1800562 and TMPRSS6 rs855791 are the main determinants of HFE and TMPRSS6 related variation in serum iron, ferritin, transferrin saturation, and total iron binding capacity. These SNPs are associated with the ratios hepcidin/ferritin (p<1×10(-5)) and hepcidin/transferrin saturation (p<1×10(-3)), but not with serum hepcidin (p>0.2). Adjustment for hepcidin or the ratio hepcidin/ferritin did not decrease the strength of the SNP-iron parameter associations.

Conclusions: Our results do not support an intermediate role for hepcidin in the SNP-iron parameter associations, which confirms previous findings, and indicate a pleiotropic SNP effect on the hepcidin ratios and the iron parameters. Taken together, this suggests that there might be other, yet unknown, serum hepcidin independent mechanisms which play a role in the association of HFE and TMPRSS6 variants with serum iron parameters.

Keywords: Complex traits; Genetic epidemiology; Haematology (incl Blood transfusion).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cohort Studies
  • Female
  • Ferritins / blood*
  • Genome-Wide Association Study
  • Hemochromatosis Protein
  • Hepcidins / blood*
  • Histocompatibility Antigens Class I / genetics*
  • Humans
  • Iron / blood
  • Iron / metabolism*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Netherlands
  • Polymorphism, Single Nucleotide
  • Serine Endopeptidases / genetics*


  • HFE protein, human
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • Ferritins
  • Iron
  • Serine Endopeptidases
  • TMPRSS6 protein, human