Genetic adaptation to extreme hypoxia: study of high-altitude pulmonary edema in a three-generation Han Chinese family - PubMed (original) (raw)

Genetic adaptation to extreme hypoxia: study of high-altitude pulmonary edema in a three-generation Han Chinese family

V Felipe Lorenzo et al. Blood Cells Mol Dis. 2009 Nov-Dec.

Erratum in

Abstract

Organismal response to hypoxia is essential for critical regulation of erythropoiesis, other physiological functions, and survival. There is evidence of individual variation in response to hypoxia as some but not all of the affected individuals develop polycythemia, and or pulmonary and cerebral edema. A significant population difference in response to hypoxia exist as many highland Tibetan, Ethiopian, and Andean natives developed adaptive mechanisms to extreme hypoxia. A proportion of non-adapted individuals exposed to high altitude develop pulmonary edema (HAPE), pulmonary hypertension, cerebral edema, and extreme polycythemia. The isolation of causative gene(s) responsible for HAPE and other extreme hypoxia complications would provide a rational basis for specific targeted therapy of HAPE, allow its targeted prevention for at-risk populations, and clarify the pathophysiology of other hypoxic maladaptations. The only suggested genetic linkage among unrelated individuals with HAPE has been with endothelial nitric oxide synthase (eNOS) gene. Here we describe a family with multiple members affected with HAPE in three generations. Families with multiple affected members with HAPE have not been described. We first ruled out linkage of HAPE with the eNOS gene. We then performed an analysis of the whole genome using high-density SNP arrays (Affymetrix v5.0) and, assuming a single gene causation of HAPE, ruled out linkage with 34 other candidate genes. Only the HIF2A haplotype was shared by individuals who exhibit the HAPE phenotype, and work on its possible causative role in HAPE is in progress. The small size of our family does not provide sufficient power for a conclusive analysis of linkage. We hope that collaboration with other investigators with access to more HAPE patients will lead to the identification of gene(s) responsible for HAPE and possibly other maladaptive hypoxic complications.

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Figures

Figure 1

Figure 1. Hypoxia Inducible Factor (HIF) pathways

A. In normoxia HIF hydroxylation and degradation occurs in the cytoplasm which involves, independent oxidation reduction of ascorbic acid (Asc) and iron (Fe). Fe then binds to prolyl hydroxylase (PHD2) forming a complex with 2-oxoglutarate (2OG) and oxygen, this complex in turn hydroxylate HIFA with 2 by products succinate and carbon dioxide. Unbound hydroxylated HIFA binds with the von Hippel-Lindau-Elongin B-Elongin C complex ubiquinating HIFA for proteosomal degradation. B. While in Hypoxia HIFA enters the nucleus for hydroxylation and escape degradation, PHDs binds to Fe, 2-oxoglutarate (2OG) and ascorbic acid but not oxygen. The protein inhibitor of growth 4 (ING4) binding to PHD2 may regulate HIFA transcriptional activity and blocks HIFA-HIFB complex binding. When HIFA and HIFB binding occurs the HIF dimer can activate the gene in the hypoxia response element (HRE) site, activating HIFA dependent genes where protein levels were upregulated like HIFA and PHD2.

Figure 1

Figure 1. Hypoxia Inducible Factor (HIF) pathways

A. In normoxia HIF hydroxylation and degradation occurs in the cytoplasm which involves, independent oxidation reduction of ascorbic acid (Asc) and iron (Fe). Fe then binds to prolyl hydroxylase (PHD2) forming a complex with 2-oxoglutarate (2OG) and oxygen, this complex in turn hydroxylate HIFA with 2 by products succinate and carbon dioxide. Unbound hydroxylated HIFA binds with the von Hippel-Lindau-Elongin B-Elongin C complex ubiquinating HIFA for proteosomal degradation. B. While in Hypoxia HIFA enters the nucleus for hydroxylation and escape degradation, PHDs binds to Fe, 2-oxoglutarate (2OG) and ascorbic acid but not oxygen. The protein inhibitor of growth 4 (ING4) binding to PHD2 may regulate HIFA transcriptional activity and blocks HIFA-HIFB complex binding. When HIFA and HIFB binding occurs the HIF dimer can activate the gene in the hypoxia response element (HRE) site, activating HIFA dependent genes where protein levels were upregulated like HIFA and PHD2.

Figure 2

Figure 2. Pedigree chart of HAPE affected family

Shaded and unshaded figures indicate affected and unaffected individual respectively. Numeric paired values represent the genotype alignment of the 3 eNOS microsatellite markers used to rule out association with HAPE.

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