A Novel EGLN1/PHD2 High-Frequency Variant in Tibetans Protects Against Hypoxia-Induced Polycythemia.

Abstract 2079

The hypoxic response, mediated by hypoxia inducible transcription factors (HIFs), is central to the control and development of many essential biological functions, including erythropoiesis. As a high altitude population, Tibetans are genetically adapted to the environmental stress of high altitude, having normal hemoglobin concentration both at sea level and at high altitude. Several haplotypes have undergone positive selection in Tibetans, including variations at or near the EGLN locus, which encodes prolyl 4-hydroxylase (PHD2). PHD2 triggers the degradation of hypoxia-inducible factors (HIFs) that mediate many physiological responses to hypoxia, including erythropoiesis.

We now describe two high-frequency Tibetan variants, PHD2^D4E and PHD2^C127S, that originated on the same haplotype about ∼6,000 years ago and contribute functionally to the Tibetan high-altitude phenotype. The PHD2^{D4E, C127S} variant exhibits a lower K_m value for O₂, suggesting that it promotes HIF degradation under hypoxia. Because HIF directly stimulates erythropoiesis, the measured kinetic PHD2^{D4E, C127S} properties were experimentally reproduced in native PHD2^{D4E, C127S} erythroid progenitors that had decreased proliferation under hypoxic conditions, whereas wild-type progenitors have increased proliferation. Our results demonstrate that the Tibetan selected PHD2^{D4E, C127S} variant contributes to protection from polycythemia at high altitude.

We describe the first high-altitude adaptive mutations in Tibetans and demonstrate that they abrogate hypoxia-induced HIF-mediated augmentation of erythropoiesis, explaining Tibetan protection from polycythemia at high altitude.