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.