Iron deficiency modifies gene expression variation induced by augmented hypoxia sensing

Blood Cells Mol Dis. 2014 Jan;52(1):35-45. doi: 10.1016/j.bcmd.2013.07.016. Epub 2013 Aug 28.


In congenital Chuvash polycythemia (CP), VHL(R200W) homozygosity leads to elevated hypoxia inducible factor (HIF) levels at normoxia. CP is often treated by phlebotomy resulting in iron deficiency, permitting us to examine the separate and synergistic effects of iron deficiency and HIF signaling on gene expression. We compared peripheral blood mononuclear cell gene expression profiles of eight VHL(R200W) homozygotes with 17 wildtype individuals with normal iron status and found 812 up-regulated and 2120 down-regulated genes at false discovery rate of 0.05. Among differential genes we identified three major gene regulation modules involving induction of innate immune responses, alteration of carbohydrate and lipid metabolism, and down-regulation of cell proliferation, stress-induced apoptosis and T-cell activation. These observations suggest molecular mechanisms for previous observations in CP of lower blood sugar without increased insulin and low oncogenic potential. Studies including 16 additional VHL(R200W) homozygotes with low ferritin indicated that iron deficiency enhanced the induction effect of VHL(R200W) for 50 genes including hemoglobin synthesis loci but suppressed the effect for 107 genes enriched for HIF-2 targets. This pattern is consistent with potentiation of HIF-1α protein stability by iron deficiency but a trend for down-regulation of HIF-2α translation by iron deficiency overriding an increase in HIF-2α protein stability.

Keywords: Chuvash polycythemia; Gene expression; Hypoxia inducible factor; Hypoxia-sensing; Iron deficiency; VHL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anemia, Iron-Deficiency / etiology
  • Anemia, Iron-Deficiency / genetics*
  • Anemia, Iron-Deficiency / immunology
  • Anemia, Iron-Deficiency / metabolism
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blood Glucose / metabolism
  • Gene Expression Regulation
  • Homozygote
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / immunology
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunity, Innate
  • Insulin / blood
  • Iron / metabolism*
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / pathology
  • Phlebotomy / adverse effects
  • Polycythemia / congenital*
  • Polycythemia / genetics
  • Polycythemia / immunology
  • Polycythemia / metabolism
  • Polycythemia / pathology
  • Protein Stability
  • Signal Transduction
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Blood Glucose
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • endothelial PAS domain-containing protein 1
  • Iron
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human

Supplementary concepts

  • Erythrocytosis, Familial, 2

Associated data

  • GEO/GSE40227