Metabolic insight into mechanisms of high-altitude adaptation in Tibetans

Abstract

Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Genetic variants/haplotypes within regions containing three of these genes (EPAS1, EGLN1, and PPARA) are associated with relatively decreased hemoglobin levels observed in Tibetans at high altitude, providing corroborative evidence for genetic adaptation to this extreme environment. The mechanisms that afford adaptation to high-altitude hypoxia, however, remain unclear. Considering the strong metabolic demands imposed by hypoxia, we hypothesized that a shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would improve adaptation to decreased oxygen availability. Correlations between serum free fatty acid and lactate concentrations in Tibetan groups living at high altitude and putatively selected haplotypes provide insight into this hypothesis. An EPAS1 haplotype that exhibits a signal of positive selection is significantly associated with increased lactate concentration, the product of anaerobic glycolysis. Furthermore, the putatively advantageous PPARA haplotype is correlated with serum free fatty acid concentrations, suggesting a possible decrease in the activity of fatty acid oxidation. Although further studies are required to assess the molecular mechanisms underlying these patterns, these associations suggest that genetic adaptation to high altitude involves alteration in energy utilization pathways.

Fig. 1

Association of previously identified adaptive haplotypes and metabolites. A) Lactate concentration is plotted against the group of putatively advantageous haplotypes (0, 1, or 2) at the EPAS1 locus. B) Serum free fatty acid concentration (FFA) is plotted against the number of putatively advantageous PPARA haplotype copies (0–2). A box-and-whisker plot overlying the data points shows the median, upper and lower quartiles, and extreme measurements as a red line, boxed ends, and dashed lines, respectively.