DNA Methylation Changes Are Associated With an Incremental Ascent to High Altitude

Abstract

Genetic and nongenetic factors are involved in the individual ability to physiologically acclimatize to high-altitude hypoxia through processes that include increased heart rate and ventilation. High-altitude acclimatization is thought to have a genetic component, yet it is unclear if other factors, such as epigenetic gene regulation, are involved in acclimatization to high-altitude hypoxia in nonacclimatized individuals. We collected saliva samples from a group of healthy adults of European ancestry (n = 21) in Kathmandu (1,400 m; baseline) and three altitudes during a trek to the Everest Base Camp: Namche (3,440 m; day 3), Pheriche (4,240 m; day 7), and Gorak Shep (5,160 m; day 10). We used quantitative bisulfite pyrosequencing to determine changes in DNA methylation, a well-studied epigenetic marker, in LINE-1, <i>EPAS1</i>, <i>EPO</i>, <i>PPARa</i>, and <i>RXRa</i>. We found significantly lower DNA methylation between baseline (1,400 m) and high altitudes in LINE-1, <i>EPO</i> (at 4,240 m only), and <i>RXRa</i>. We found increased methylation in <i>EPAS1</i> (at 4,240 m only) and <i>PPARa</i>. We also found positive associations between <i>EPO</i> methylation and systolic blood pressure and <i>RXRa</i> methylation and hemoglobin. Our results show that incremental exposure to hypoxia can affect the epigenome. Changes to the epigenome, in turn, could underlie the process of altitude acclimatization.