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Gain-of-function EGLN1 prolyl hydroxylase (PHD2 D4E:C127S) in combination with EPAS1 (HIF-2α) polymorphism lowers hemoglobin concentration in Tibetan highlanders
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نویسنده
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Tashi Tsewang ,Reading N. Scott ,Wuren Tanna ,Zhang Xu ,Moore Lorna G. ,Hu Hao ,Tang Feng ,Shestakova Anna ,Lorenzo Felipe ,Burjanivova Tatiana ,Koul Parvaiz ,Guchhait Prasenjit ,Wittwer Carl T. ,Julian Colleen G. ,Shah Binal ,Huff Chad D. ,Gordeuk Victor R. ,Prchal Josef T. ,Ge RiLi
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منبع
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journal of molecular medicine - 2017 - دوره : 95 - شماره : 6 - صفحه:665 -670
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چکیده
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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.
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کلیدواژه
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High altitude ,Genetic adaptation ,Polycythemia ,Hypoxia ,High-resolution melting assay
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آدرس
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University of Utah, Division of Hematology, USA, University of Utah, Division of Hematology, Department of Pathology and ARUP Laboratories, USA, Qinghai University, China, University of Illinois at Chicago, Division of Hematology and Oncology, Department of Medicine, USA, University of Colorado Denver, Departments of Medicine and Obstetrics/Gynecology, USA, University of Texas, USA, Qinghai University, China, University of Utah, Department of Pathology and ARUP Laboratories, USA, University of Utah, Division of Hematology, USA, University of Utah, Division of Hematology, USA. Comenius University in Bratislava, Department of Molecular Biology, Slovakia, Sher-i-Kashmir Institute of Medical Sciences, India, Regional Centre for Biotechnology, India, University of Utah, Department of Pathology and ARUP Laboratories, USA, University of Colorado Denver, Departments of Medicine and Obstetrics/Gynecology, USA, University of Illinois at Chicago, Division of Hematology and Oncology, Department of Medicine, USA, University of Texas, USA, University of Illinois at Chicago, Division of Hematology and Oncology, Department of Medicine, USA, University of Utah, Division of Hematology, Department of Pathology and ARUP Laboratories, USA. Charles University in Prague, Department of Pathophysiology and 1st Department of Medicine, Czech Republic. University of Utah School of Medicine, USA, Qinghai University, China
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Authors
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