title: Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders.
abstract: 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.
  
  
  
  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.
authors.affiliation: Division of Hematology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Tsewang
authors.initials: T
authors.lastname: Tashi
authors.affiliation: Division of Hematology, University of Utah, Salt Lake City, UT, USA.|Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: N
authors.initials: N
authors.lastname: Scott Reading
authors.affiliation: Research Center for High-Altitude Medicine, Qinghai University, Xining, China.
authors.forename: Tanna
authors.initials: T
authors.lastname: Wuren
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Medicine and Obstetrics/Gynecology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Lorna G
authors.initials: LG
authors.lastname: Moore
authors.affiliation: MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Research Center for High-Altitude Medicine, Qinghai University, Xining, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Shestakova
authors.affiliation: Division of Hematology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: Lorenzo
authors.affiliation: Division of Hematology, University of Utah, Salt Lake City, UT, USA.|Department of Molecular Biology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Bratislava, Slovakia.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Burjanivova
authors.affiliation: Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India.
authors.forename: Parvaiz
authors.initials: P
authors.lastname: Koul
authors.affiliation: Regional Centre for Biotechnology, Faridabad, Haryana, India.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Guchhait
authors.affiliation: Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, UT, USA.
authors.forename: Carl T
authors.initials: CT
authors.lastname: Wittwer
authors.affiliation: Departments of Medicine and Obstetrics/Gynecology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Julian
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Binal
authors.initials: B
authors.lastname: Shah
authors.affiliation: MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: Chad D
authors.initials: CD
authors.lastname: Huff
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
authors.affiliation: Division of Hematology, University of Utah, Salt Lake City, UT, USA. josef.prchal@hsc.utah.edu.|Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, UT, USA. josef.prchal@hsc.utah.edu.|Department of Pathophysiology and 1st Department of Medicine, 1st Faculty Medicine, Charles University in Prague, Prague, Czech Republic. josef.prchal@hsc.utah.edu.|Hematology, SOM 5C310, University of Utah School of Medicine, Salt Lake City, UT, 84132-2408, USA. josef.prchal@hsc.utah.edu.
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.affiliation: Research Center for High-Altitude Medicine, Qinghai University, Xining, China. geriligao@hotmail.com.
authors.forename: RiLi
authors.initials: R
authors.lastname: Ge
mesh_terms: D000064:Acclimatization / Q000235:genetics*; D000328:Adult; D000531:Altitude; D044466:Asian People / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D004921:Erythropoietin / Q000097:blood; D005260:Female; D005293:Ferritins / Q000097:blood; D059647:Gene-Environment Interaction; D006239:Haplotypes; D006454:Hemoglobins / Q000032:analysis*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018609:Tibet; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D005293:Ferritins; D006454:Hemoglobins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D000099162:Endothelial PAS Domain-Containing Protein 1; C490190:EGLN1 protein, human
keywords: Genetic adaptation; High altitude; High-resolution melting assay; Hypoxia; Polycythemia