Association of <i>EGLN1</i> gene with high aerobic capacity of Peruvian Quechua at high altitude.

Abstract

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 <i>Egl-9 homolog 1</i> gene (<i>EGLN1</i>) 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 <i>EGLN1</i> 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 <i>EGLN1</i> SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at <i>EGLN1</i> in Andeans, and support the hypothesis that natural selection has increased the frequency of an <i>EGLN1</i> causal variant that enhances O₂ delivery or use during exercise at altitude in Peruvian Quechua.