Abstract
The individual physiological response to high-altitude hypoxia involves both genetic and non-genetic factors, including epigenetic modifications. Epigenetic changes in hypoxia factor pathway (HIF) genes are associated with high-altitude acclimatization. However, genome-wide epigenetic changes that are associated with short-term hypoxia exposure remain largely unknown. We collected a series of DNA samples from 15 participants of European ancestry trekking to Everest Base Camp to identify DNA methylation changes associated with incremental altitude ascent. We determined genome-wide DNA methylation levels using the Illumina MethylationEPIC chip comparing two altitudes: baseline 1,400 m (day 0) and elevation 4,240 m (day 7). The results of our epigenome-wide association study revealed 2,873 significant differentially methylated positions (DMPs) and 361 significant differentially methylated regions (DMRs), including significant positions and regions in hypoxia inducible factor (HIF) and the renin–angiotensin system (RAS) pathways. Our pathway enrichment analysis identified 95 significant pathways including regulation of glycolytic process (GO:0006110), regulation of hematopoietic stem cell differentiation (GO:1902036), and regulation of angiogenesis (GO:0045765). Lastly, we identified an association between the ACE gene insertion/deletion (I/D) polymorphism and oxygen saturation, as well as average ACE methylation. These findings shed light on the genes and pathways experiencing the most epigenetic change associated with short-term exposure to hypoxia.
Highlights
Altitude acclimatization in humans is characterized by complex physiological responses, which include the cardiovascular, hemopoietic, respiratory, and metabolic systems [for review, see Palmer (2010)]
The physiological responses we have reported are expected at high altitude, i.e., lower arterial oxygen saturation due to decreased ambient PO2, a decrease in PETCO2 indicating an increase in alveolar ventilation, and higher [Hb], reflecting the body’s physiological response to low-oxygen conditions by increasing hemoglobin production
We identified significant associations between genome-wide DNA methylation and short-term altitude exposure, among which were CpG sites and regions associated with hypoxia inducible factor (HIF) pathway, including HIF1A, and renin–angiotensin system (RAS) pathway genes
Summary
Altitude acclimatization in humans is characterized by complex physiological responses, which include the cardiovascular, hemopoietic, respiratory, and metabolic systems [for review, see Palmer (2010)]. Cardiovascular output increases (i.e., increased heart rate and stroke volume) upon initial altitude exposure and DNA Methylation High-Altitude Acclimatization returns to pre-altitude baseline after several days of acclimatization [for review, see Naeije (2010)]. The hemopoietic response in the form of increased erythrocyte production is evident after several days to weeks of exposure (Rodriguez et al, 2000). Each of these responses facilitates acute acclimatization to the low ambient oxygen tension present at high altitudes, allowing humans to acclimatize to hypoxic conditions
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