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

Abstract. The endothelial PAS domain protein 1 (EPAS1) gene functions to sense the blood oxygen level by regulating the hypoxia-inducible transcription factor pathway, and single nucleotide polymorphisms (SNPs) of EPAS1 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 EPAS1 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 EPAS1 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. EPAS1 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 EPAS1 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.

The relationship between anxiety and acute mountain sickness

“…It is interesting that trait STAI Y-2 scores and not state STAI Y-1 scores, taken at the study baseline altitude of 848m, were predictive of future risk of severe AMS. This is perhaps not surprising, given that susceptibility to AMS appears to be a relatively stable individual trait with increasing evidence for a genetic predisposition that can be influenced by additional factors such as ascent profile [ 28 – 30 ]. We found that trait anxiety and STAI Y-2 questions, as opposed to STAI Y-1 was a predictor of future AMS given its representation of more stable individual trait anxiety levels [ 23 ].…”

EPAS1 and VEGFA gene variants are related to the symptoms of acute mountain sickness in Chinese Han population: a cross-sectional study

“…Based on LD analyses, tag SNPs which represented neighboring SNPs in the genomic region were retained. In EGLN1 , we selected rs2066140, rs508618, rs1538667, rs1339891 and rs2275279 which located in introns, rs2153364, rs1361384 and rs1339894 at 5′-UTR, rs12757362 and at the upstream of the gene [ 8 , 10 , 12 , 18 ]. In EPAS1 , we selected rs13419896, rs4953354 and rs6756667 in introns and rs1868092 at the downstream of the gene [ 7 , 12 , 19 ].…”

“…Moreover, few studies have examined the genetic component of susceptibility to AMS in lowlanders, such as the Chinese Han population, following acute exposure to HA. Our group showed that SNPs in EPAS1 and the 5′-untranslated region (UTR) of EGLN1 may be associated with a high risk of AMS [ 17 , 18 ]. Ding et al [ 19 ] reported a possible relationship between VEGFA polymorphisms and AMS in a relatively small Chinese Han population.…”

Association of Hypoxia-Inducible Factor-2 Alpha Gene Polymorphisms with the Risk of Hepatitis B Virus-Related Liver Disease in Guangxi Chinese: A Case-Control Study

“…Genetic polymorphisms are considered the main genetic elements involved in the development of various kinds of diseases [ 26 ]. To date, several studies have reported associations between HIF-2a gene polymorphisms and renal cell carcinoma [ 27 ], prostate cancer [ 28 ], lungadenocarcinoma [ 29 ], non-small-cell lung cancer [ 30 ], acute mountainsickness [ 31 ], and maximum metabolic performance in elite endurance athletes [ 32 ]. However, HIF-2a gene polymorphisms’ involvement in HBV-related diseases remains elusive.…”