Association of 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 (VOmax) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated gene () as a candidate gene. The encoded protein, EGLN1/PHD2, is an O sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 SNPs associated with higher VOmax (L⋅min and mL⋅min⋅kg) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VOmax) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VOmax genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min⋅kg vs. CC = 30.5 mL⋅min⋅kg). To guard against spurious association, we controlled for population stratification. Findings were replicated for SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at in Andeans, and support the hypothesis that natural selection has increased the frequency of an causal variant that enhances O delivery or use during exercise at altitude in Peruvian Quechua.