Genetic variants of endothelial PAS domain protein 1 are associated with susceptibility to acute mountain sickness in individuals unaccustomed to high altitude: A nested case-control study

Abstract

The endothelial PAS domain protein 1 (<i>EPAS1</i>) gene functions to sense the blood oxygen level by regulating the hypoxia-inducible transcription factor pathway, and single nucleotide polymorphisms (SNPs) of <i>EPAS1</i> have been found to have a strong and positive selection in the adaptation of the native Tibetan highland population to high-altitude hypoxia. The aim of the present study was to investigate the effect of <i>EPAS1</i> SNPs on the risk of acute mountain sickness (AMS) and the physiological responses to acute high-altitude hypoxia in lowland humans. Three tag SNPs (rs6756667, rs13419896 and rs4953354; minor allele frequency, ≥5%) were selected and genotyped in 603 unrelated Han Chinese men, who had traveled to Lhasa (a high-altitude hypoxia environment) by plane, using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry method. The data showed that the <i>EPAS1</i> rs6756667 wild-type GG homozygous genotype was associated with elevated AMS risk compared with the AA and AG genotypes (odds ratio, 1.815; 95% confidence interval, 1.233-2.666; P=0.0023) using the dominant-model analysis. <i>EPAS1</i> rs6756667 GG genotypes were also associated with higher levels of hemoglobin, red blood cells and hematocrit than those carrying the AG heterozygote during AMS development. These findings indicate that <i>EPAS1</i> SNPs play a role in the physiological effects of AMS, and these effects could be further evaluated as a therapeutic strategy to control acute hypoxia-related human diseases.