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 Molecular Biology Jessenius Faculty of Medicine in Martin Comenius University in Bratislava Bratislava Slovakia

Department of Pathology and ARUP Laboratories University of Utah Salt Lake City UT USA

Department of Pathophysiology and 1st Department of Medicine 1st Faculty Medicine Charles University Prague Prague Czech Republic

Departments of Medicine and Obstetrics Gynecology University of Colorado Denver Aurora CO USA

Division of Hematology and Oncology Department of Medicine University of Illinois at Chicago Chicago IL 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

Sher i Kashmir Institute of Medical Sciences Srinagar India

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