Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders
Language English Country Germany Media print-electronic
Document type Journal Article
Grant support
K12 HD057022
NICHD NIH HHS - United States
R01 HL138181
NHLBI NIH HHS - United States
P01 CA108671
NCI NIH HHS - United States
PubMed
28233034
DOI
10.1007/s00109-017-1519-3
PII: 10.1007/s00109-017-1519-3
Knihovny.cz E-resources
- Keywords
- Genetic adaptation, High altitude, High-resolution melting assay, Hypoxia, Polycythemia,
- MeSH
- Acclimatization genetics MeSH
- Asian People genetics MeSH
- Adult MeSH
- Erythropoietin blood MeSH
- Ferritins blood MeSH
- Haplotypes MeSH
- Hemoglobins analysis MeSH
- Gene-Environment Interaction MeSH
- Polymorphism, Single Nucleotide MeSH
- Humans MeSH
- Altitude MeSH
- Hypoxia-Inducible Factor-Proline Dioxygenases genetics MeSH
- Basic Helix-Loop-Helix Transcription Factors genetics MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Tibet MeSH
- Names of Substances
- EGLN1 protein, human MeSH Browser
- endothelial PAS domain-containing protein 1 MeSH Browser
- Erythropoietin MeSH
- Ferritins MeSH
- Hemoglobins MeSH
- Hypoxia-Inducible Factor-Proline Dioxygenases MeSH
- Basic Helix-Loop-Helix Transcription Factors MeSH
UNLABELLED: Tibetans have lived at high altitude for generations and are thought to be genetically adapted to hypoxic environments. Most are protected from hypoxia-induced polycythemia, and a haplotype of EPAS1, encoding hypoxia-inducible factor (HIF-2α), has been associated with lower hemoglobin levels. We earlier reported a Tibetan-specific EGLN1 haplotype encoding PHD2 which abrogates HIF augmentation in hypoxia. We genotyped 347 Tibetan individuals from varying altitudes for both the Tibetan-specific EGLN1 haplotype and 10 candidate SNPs in the EPAS1 haplotype and correlated their association with hemoglobin levels. The effect of the EGLN1 haplotype on hemoglobin exhibited age dependency at low altitude, while at higher altitudes, it showed a trend to lower hemoglobin levels in the presence of the Tibetan-selected EPAS1 rs142764723 C/C allele. The observed gene-environment and gene-gene interactions and the moderate effect of the EGLN1 and EPAS1 haplotypes on hemoglobin indicate that other modifiers exist. It remains to be determined whether a blunting of erythropoiesis or other physiological consequences of HIF downregulation are the primary drivers of these genetic adaptations among Tibetans. KEY MESSAGE: Most Tibetans are protected from polycythemia while living in high altitude. An EGLN1 co-adapted haplotype, EGLN1 c.12C>G, c.380G>C is uniquely Tibetan. The Tibetan EPAS1 haplotype has introgressed from the Denisovan genome. While EGLN1 and EPAS1 genotypes lower Hb, this study indicates additional Hb modifiers.
Department of Pathology and ARUP Laboratories University of Utah Salt Lake City UT USA
Departments of Medicine and Obstetrics Gynecology University of Colorado Denver Aurora CO USA
Division of Hematology University of Utah Salt Lake City UT USA
Hematology SOM 5C310 University of Utah School of Medicine Salt Lake City UT 84132 2408 USA
MD Anderson Cancer Center University of Texas Houston TX USA
Regional Centre for Biotechnology Faridabad Haryana India
Research Center for High Altitude Medicine Qinghai University Xining China
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