Genetic variability of hypoxia-inducible factor alpha (HIFA) genes in familial erythrocytosis: Analysis of the literature and genome databases

Eur J Haematol. 2019 Oct;103(4):287-299. doi: 10.1111/ejh.13304. Epub 2019 Aug 23.


Familial erythrocytosis (FE) is a congenital disorder, defined by elevated red blood cell number, hemoglobin, and hematocrit. Among eight types of FE, type 4 is caused by variants in the EPAS1 gene. Two other hypoxia-inducible factor alpha (HIFA) subunits, HIF1A and HIF3A, have not yet been associated with medical history of FE, but have potential role in the development of erythrocytosis. To improve diagnosis, it is crucial to identify new variants in genes involved in erythrocyte production. Published literature and data from genome browsers were used to obtain HIFA sequence variants associated with erythrocytosis and to locate them on protein sequence and regulatory sites. We retrieved 24 variants from the literature: 2 in HIF1A, 20 in EPAS1 and 2 in HIF3A gene. Sixteen out of 20 variants in the EPAS1 gene are positioned in a conserved region of 13 amino acids within exon 12, next to regulatory post-translational modification and binding sites, suggesting that EPAS1 has an important role in erythropoiesis. The role of HIF1A and HIF3A in the development of erythrocytosis should be further investigated.

Keywords: HIFA; familial erythrocytosis; genetic variability; hypoxia-inducible factor; sequence variant.

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Databases, Genetic
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genomics / methods
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Polycythemia / congenital*
  • Polycythemia / diagnosis
  • Polycythemia / genetics
  • Polycythemia / therapy
  • Repressor Proteins / genetics


  • Apoptosis Regulatory Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • HIF3A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • endothelial PAS domain-containing protein 1

Supplementary concepts

  • Polycythemia, primary familial and congenital

Associated data

  • GENBANK/NM_001530.4
  • GENBANK/NM_001430.5
  • GENBANK/NM_001430.4
  • GENBANK/NM_152795.3