Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude and this may be a reflection of genetic adaptation to chronic hypoxia. Previous genome-wide (GW) scans for natural selection have nominated EGLN1 as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-a (HIF-a), which regulates the cellular response to hypoxia. From GWAS and ANCOVA performed on a total sample that included n=429 Peruvian Quechua and n=94 US lowland referents, we identified five EGLN1 SNPs associated with higher VO2max (l.min-1 and ml.min-1.kg-1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For four of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared to 25 diverse lowland comparison populations from the 1000 Genomes project. Genotype effects were substantial with high versus low VO2max genotype categories differing by ...