Hereditary hemochromatosis type 1 phenotype modifiers in Italian patients. The controversial role of variants in HAMP, BMP2, FTL and SLC40A1 genes

Blood Cells Mol Dis. 2015 Jun;55(1):71-5. doi: 10.1016/j.bcmd.2015.04.001. Epub 2015 Apr 16.


Hereditary hemochromatosis (HH) is a heterogeneous disorder of iron metabolism. The most common form of the disease is Classic or type 1 HH, mainly caused by a biallelic missense p.Cys282Tyr (c.845G>A) mutation in the HFE gene. However, the penetrance of p.Cys282Tyr/p.Cys282Tyr genotype is incomplete in terms of both biochemical and clinical expressivity. Lack of penetrance is thought to be caused by several genetic and environmental factors. Recently, a lot of evidences on HH genetic modifiers were produced, often without conclusive results. We investigated 6 polymorphisms (rs10421768 in HAMP gene, rs235756 in BMP2 gene, rs2230267 in FTL gene, rs1439816 in SLC40A1 gene, rs41295942 in TFR2 gene and rs2111833 in TMPRSS6 gene) with uncertain function in order to further evaluate their role in an independent cohort of 109 HH type 1 patients. Our results make it likely the role of rs10421768, rs235756, rs2230267 and rs1439816 polymorphisms, respectively in HAMP, BMP2, FTL and SLC40A1 genes in HH expressivity. In addition, previous and our findings support a hypothetical multifactorial model of HH, characterized by a principal gene (HFE in HH type 1) and minor genetic and environmental factors that still have to be fully elucidated.

Keywords: BMP2; FTL; HAMP; Hereditary hemochromatosis; Iron overload; Penetrance defect; SLC40A1; TFR2; TMPRSS6; p.Cys282Tyr.

MeSH terms

  • Alleles
  • Apoferritins / genetics*
  • Bone Morphogenetic Protein 2 / genetics*
  • Cation Transport Proteins / genetics*
  • Female
  • Ferritins / blood
  • Gene Frequency
  • Gene-Environment Interaction
  • Genotype
  • Hemochromatosis / blood
  • Hemochromatosis / genetics*
  • Hemochromatosis / pathology
  • Hemochromatosis Protein
  • Hepcidins / genetics*
  • Histocompatibility Antigens Class I / genetics*
  • Humans
  • Iron / blood
  • Male
  • Membrane Proteins / genetics*
  • Penetrance
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Receptors, Transferrin / genetics
  • Serine Endopeptidases / genetics
  • Transferrin / metabolism


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Cation Transport Proteins
  • FTL protein, human
  • HAMP protein, human
  • HFE protein, human
  • Hemochromatosis Protein
  • Hepcidins
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • Receptors, Transferrin
  • TFR2 protein, human
  • Transferrin
  • metal transporting protein 1
  • Ferritins
  • Apoferritins
  • Iron
  • Serine Endopeptidases
  • TMPRSS6 protein, human