Genetic Variants in EPAS1 Contribute to Adaptation to High-Altitude Hypoxia in Sherpas

Abstract

Sherpas comprise a population of Tibetan ancestry in the Himalayan region that is renowned for its mountaineering prowess. The very small amount of available genetic information for Sherpas is insufficient to explain their physiological ability to adapt to high-altitude hypoxia. Recent genetic evidence has indicated that natural selection on the endothelial PAS domain protein 1 (EPAS1) gene was occurred in the Tibetan population during their occupation in the Tibetan Plateau for millennia. Tibetan-specific variations in EPAS1 may regulate the physiological responses to high-altitude hypoxia via a hypoxia-inducible transcription factor pathway. We examined three significant tag single-nucleotide polymorphisms (SNPs, rs13419896, rs4953354, and rs4953388) in the EPAS1 gene in Sherpas, and compared these variants with Tibetan highlanders on the Tibetan Plateau as well as with non-Sherpa lowlanders. We found that Sherpas and Tibetans on the Tibetan Plateau exhibit similar patterns in three EPAS1 significant tag SNPs, but these patterns are the reverse of those in non-Sherpa lowlanders. The three SNPs were in strong linkage in Sherpas, but in weak linkage in non-Sherpas. Importantly, the haplotype structured by the Sherpa-dominant alleles was present in Sherpas but rarely present in non-Sherpas. Surprisingly, the average level of serum erythropoietin in Sherpas at 3440 m was equal to that in non-Sherpas at 1300 m, indicating a resistant response of erythropoietin to high-altitude hypoxia in Sherpas. These observations strongly suggest that EPAS1 is under selection for adaptation to the high-altitude life of Tibetan populations, including Sherpas. Understanding of the mechanism of hypoxia tolerance in Tibetans is expected to provide lights to the therapeutic solutions of some hypoxia-related human diseases, such as cardiovascular disease and cancer.

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

“…It was found that the rs6756667 GG genotype significantly increased the risk of developing AMS compared with the AA and heterozygous AG genotypes. The present results are consistent with those of a previous study involving individuals of a Tibetan ethnicity, including Sherpas, that was performed by Hanaoka et al (28). Previous genome-wide studies have revealed that the rs6756667 polymorphism is significantly associated with high-altitude adaptation in Tibetans (8,14).…”

“…Furthermore, Beall et al (8) investigated 31 SNPs, including rs6756667, and the data showed a significant association with the blood levels of Hb in Tibetans. Results from Hanaoka et al (28) indicated that EPAS1 was under selection for adaptation to the high-altitude life of the Sherpa population. Bioinformatics analysis (http://www.generegulation.com/pub/programs.html; http://motif.genome.ad.jp) has revealed that the rs6756667 site contains a non-functional domain, but cis-element activity regulates EPAS1 expression by binding certain transcription factors (CREB, CRB-BP or v-ErbA); however, additional functional studies are necessary to clarify this theory.…”

Human high-altitude adaptation: forward genetics meets the HIF pathway

“…Two genes in particular, ARNT2 and THRB, show suggestive relationships with hemoglobin concentration; for example, Ethiopian Amhara with two copies of the THRB rs826216 C allele display hemoglobin levels that are higher than those in individuals with two copies of the T allele (Scheinfeldt et al 2012). Recent research also has identified HIF pathway candidate genes showing signatures of natural selection in other human populations, including Sherpa, Indians, and Mongolians (Aggarwal et al 2010;Hanaoka et al 2012;Kang et al 2013;Xing et al 2013;Jeong et al 2014). ADRA1B EDNRA IL1B NOTCH1 SATB1 ARNT2 EDNRB IL6 NRP1 SNAI3 ATP1A1 EGLN1 KCNMA1 NRP2 SPRY2 ATP1A2 EGLN2 MDM2 PIK3CA TF CDH1 ELF2 MMP2 POLR2A TGFA COPS5 IGFBP1 MTOR PRKAA1 TNC CXCR4 IGFBP2 NOS1 PRKAA2 TNF EDN1 IL1A NOS2 PSMC3 EGLN3 HMOX2 NOS2 POLR2A ARNT EP300 IGFBP1 NRP1 PPARA ANGPTL4 EPAS1 IGFBP2 NRP2 RBX1 CASR EPO IL1A PDGF2 TNC COPS5 FLT1 IL1B PGF TNF EDN1 HBB IL6 PIK3CB VEGFA EDNRA HBG2 MDM2 PIK3CG VEGFC EGLN1 HIF1A NOS1 PKLR a Data are from Bigham et al (2009Bigham et al ( , 2010.…”

Oxygen enrichment and its application to life support systems for workers in high-altitude areas

“…[1][2][3] Hypoxia is involved the major biological pathways that contribute to human pathogeneses of the cardiovascular system, the respiratory system, neurophysiology, oncology, transplantation, and infectious diseases. 4 When the PAO 2 of air is less than 8 kPa (60 mmHg), the arterial oxygen content (CaO 2 ) and the arterial oxygen saturation (SaO 2 ) can significantly decrease and cause hypotonic hypoxemia (low arterial oxygen pressure, low saturation of hemoglobin by oxygen, and high hematocrit and hemoglobin concentrations). 5 This most commonly occurs at high altitudes because both the atmospheric pressure and the PAO 2 of air decreases with increased elevation.…”