The Tibetan PHD2 Polymorphism Asp4Glu Is Associated with Hypersensitivity of Erythroid Progenitors to EPO and Upregulation of HIF-1 Regulated Genes Hexokinase (HK1) and Glucose Transporter 1 (SLC2A/GLUT1),

Abstract 3388

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, many Tibetans have developed a remarkable ability to protect against several hypoxic complications, including polycythemia and other harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia. We have identified 10 genes involved in high-altitude adaptation in Tibetans, including a principal negative regulator of HIF-1a and HIF-2 a peptides, i.e. PHD2 (EGLN1), as well as HIF2A (EPAS1) (Simonson, Science 2010). At this meeting last year (Lorenzo, Abstract# 2602 ASH 2010), we reported a novel PHD2 Asp4Glu mutation that we found in 57 of 94 Tibetan, 2 of 88 Asian and 0 of 38 Caucasian chromosomes. In most Tibetan samples, this variant is associated with a previously reported, unvalidated PHD2 polymorphism, Cys127Ser (found in 70 of 94 Tibetan, 27 of 88 Asian and 4 of 38 Caucasian chromosomes).

To study the functional consequences of this PHD2 Asp4Glu mutation, we recruited five Tibetan volunteers living in Utah, four of whom were homozygous and 1 heterozygous for PHD2 Asp4Glu and Cys127Ser. We unexpectedly found that homozygotes for the exon 1 PHD2 mutation had markedly hypersensitive erythroid BFU-E (Fig.1) compared to the range of normal controls we have standardized over several decades. Interestingly, erythroid progenitors from individuals with Chuvash polycythemia or a HIF-2a gain-of-function mutation also have hypersensitive BFU-E. To determine if the Tibetan erythroid hypersensitivity data may be explained by increased HIF activity, we have quantified HIF target gene expression in subject granulocytes and found a significant increase in hexokinase (HK1) and glucose transporter (GLUT1/SLC2A) mRNA levels.

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These data report the first molecular defect with functional consequences that is associated with the complex Tibetan adaptation to extreme hypoxia.