title: Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru.
abstract: Painschab, Matthew S., Gary E. Malpartida, Victor G. Davila-Roman, Robert H. Gilman, Todd M. Kolb, Fabiola Leon-Velarde, J. Jaime Miranda, and William Checkley. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive erythrocytosis in high altitude Peru. High Alt Med Biol 16:26-33, 2015.-Long-term residence at high altitude is associated with the development of chronic mountain sickness (CMS), which is characterized by excessive erythrocytosis (EE). EE occurs under chronic hypoxia, and a strongly selected mutation in hypoxia-inducible factor 2α (HIF2A) has been found in native Tibetans that correlates with having a normal hemoglobin at high altitude. We sought to evaluate differences in plasma levels of four HIF-responsive proteins in 20 participants with EE (hemoglobin >21 g/dL in men and >19 in women) and in 20 healthy, age- and sex-matched participants without EE living at high altitude in Puno, Peru. We performed ELISA to measure plasma levels of the four HIF-responsive proteins: vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGF-R1), endothelin-1, and erythropoietin. As a secondary aim, we evaluated the association between HIF-responsive proteins and echocardiography-estimated pulmonary artery systolic pressure (PASP) in a subset of 26 participants. sVEGF-R1 was higher in participants with vs. without EE (mean 107 pg/mL vs. 90 pg/mL; p=0.007). Although plasma concentrations of endothelin-1, VEGF, and erythropoietin were higher in participants with vs. without EE, they did not achieve statistical significance (all p>0.25). Both sVEGF-R1 (p=0.04) and erythropoietin (p=0.04) were positively associated with PASP after adjustment for age, sex, and BMI. HIF-responsive proteins may play a pathophysiological role in altitude-related, chronic diseases but our results did not show consistent changes in all measured HIF-responsive proteins. Larger studies are needed to evaluate for additional genetic and environmental risk factors.
authors.affiliation: 1 Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University , Baltimore, Maryland.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Painschab
authors.forename: Gary E
authors.initials: GE
authors.lastname: Malpartida
authors.forename: Victor G
authors.initials: VG
authors.lastname: Dávila-Roman
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kolb
authors.forename: Fabiola
authors.initials: F
authors.lastname: León-Velarde
authors.forename: J Jaime
authors.initials: JJ
authors.lastname: Miranda
authors.forename: William
authors.initials: W
authors.lastname: Checkley
mesh_terms: D000328:Adult; D000368:Aged; D000531:Altitude; D000532:Altitude Sickness / Q000097:blood*; D051792:Basic Helix-Loop-Helix Proteins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D016022:Case-Control Studies; D019332:Endothelin-1 / Q000097:blood; D004921:Erythropoietin / Q000097:blood; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010568:Peru; D011086:Polycythemia / Q000097:blood*; D011651:Pulmonary Artery / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood; D042442:Vascular Endothelial Growth Factors / Q000097:blood; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D019332:Endothelin-1; D004921:Erythropoietin; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: EPO; HIF; VEGF; chronic mountain sickness; pulmonary hypertension