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

Significance Andean highland native populations, such as the Quechua of Peru, have enhanced exercise capacity at altitude and may be genetically adapted to altitude. We identified 5 genetic markers near the Egl-9 homolog 1 gene (EGLN1) gene that were associated with higher aerobic capacity (VO2max) in hypoxia. EGLN1 encodes for a protein that controls the level of the Hypoxia Inducible Factor-α, which in turn regulates the cellular hypoxic response. Advantageous SNP alleles were associated with a significantly higher VO2max and were found at higher frequency in Quechua compared with lowland populations. These results add further context to previous studies that have provided evidence of natural selection at the EGLN1 locus in Andeans. Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 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 EGLN1 SNPs associated with higher VO2max (L⋅min−1 and mL⋅min−1⋅kg−1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min−1⋅kg−1 vs. CC = 30.5 mL⋅min−1⋅kg−1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.