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.

Associations of high altitude polycythemia with polymorphisms in EPAS1, ITGA6 and ERBB4 in Chinese Han and Tibetan populations

“…In the plateau region, the long-term adaptation and natural selection of modern Tibetan and Han changed their genetic structure [ 19 ]. Chronic hypobaric hypoxia is the main reason of HAPC [ 20 ].…”

High-Altitude Pulmonary Vascular Diseases

“…Patients with CMS have inappropriately elevated or normal EPO concentrations in relation to their polycythemia. 79 CMS prevalence varies depending on ethnic groups. In the Andes, the prevalence is highest and increases with age and altitude of residence.…”

Towards sustainable partnerships in global health: the case of the CRONICAS Centre of Excellence in Chronic Diseases in Peru

“…In Puno, a highland Peruvian area located at 3825 m above sea level, our international team of researchers showed that excessive erythrocytosis was strongly associated with having metabolic syndrome and being overweight, besides its association with hypoxemia and lower forced vital capacity [ 43 ]. Other high altitude research includes investigations of biomarkers linked to excessive erythrocytosis [ 44 ], use of point-of-care devices for screening of excessive erythrocytosis [ 45 ], and studies of the link between hypoxemia and cardiometabolic conditions [ 46 ].…”