A Novel PHD2 Mutation Associated with Tibetan Genetic Adaptation to High Altitude Hypoxia.

Abstract 2602

The ability of the body to maintain oxygen hemostasis is essential for its survival. The body is required to adapt to the physiologic constraints imposed by a hypoxic environment in order to ensure optimal physiological functions. The study of indigenous high-altitude residents provides an opportunity to identify genes that may have play a role in hypoxia adaptation, and recent studies indicate that Tibetans have genetically adapted to the extremely hypoxic environment at high altitude. Interestingly, Tibetan adaption includes protection from polycythemia. We recently reported genome-wide scans of selection (Affymetrix Human SNP chips v6.0) for Tibetans (Simonson, Science July, 2010). At least 10 chromosomal regions were identified as likely targets for high-altitude adaptation, and two of these regions, EGLN1 (PHD2) and PPARA, were associated with protection against high-altitude polycythemia which is unique to this indigenous highland population. PHD2 is a negative regulator of the alpha subunits of HIF-1 and HIF-2 transcription factors regulating many essential functions including erythropoiesis, iron metabolism, development, in addition to other functions. A gain of function mutation of the alpha subunit of HIF-2 is associated with congenital polycythemia. We sequenced the exons of PPARA and PHD2 by direct sequencing and found two missense mutations in exon 1 of the PHD2 gene: the first is located within codon 4, and changes Aspartate to Glutamate (Asp4Glu) and the second is an unvalidated SNP (rs12097901) at codon 127 that changes Cysteine to Serine (Cy127Ser). The samples with high Hb show a heterozygous change, while the subject with normal Hb exhibited a homozygous change in both codons of the PHD2 gene.

The association of these two missense PHD2 mutations to hemoglobin level is now being evaluated by studies of a larger population of Tibetan natives and the functional effects on levels and activities of HIF-1 and HIF-2 genes evaluated by transfection of these mutated PHD2 cDNA constructs in reporter cells.