HIF2A Variants Were Associated with Different Levels of High-Altitude Hypoxia among Native Tibetans

Abstract

Hypoxia inducible factors, including HIF1A and HIF2A, play central roles in response to high-altitude hypoxia and genetic variants of HIF1A or HIF2A were associated with high-altitude sickness or adaptation. However, it remains to determine whether they are associated with tolerance to different levels of high-altitude selection pressure among native Tibetans. We recruited 189 Tibetan subjects living at 2,700 meters (Low level of high altitude, LHA), 197 at 3,200 meters (Middle level of high altitude of high altitude, MHA), 249 at 3,700 meters (High level of high altitude, HHA) and 269 at 4,700 meters (Very high level of high altitude, VHA) and performed association analysis of twelve tSNPs (tagging SNPs) in HIF1A and HIF2A with high-altitude. We found (1) a increasing trend of HIF2A rs5621780-C(18.4%, 15.9%, 32.8% and 31.1%, respectively, in LHA, MHA, HHA and VHA)(P = 3.56E-9); (2) increasing trends of HIF2A rs6756667-A(68.7%, 73.4%, 79.9% and 89.6%), rs7589621- G(74.6%, 77.9%, 83.7%, and 92.1%) and rs1868092-A(64.1%, 67.3%, 75.1% and 84.4%) (P = 3.56E-9, 4.68E-16, 1.17E-13 and 7.09E-14, respectively); (3) a increasing trend of haplotype AG (68.7%, 73.1%, 79.9% and 89.6%) (P = 2.22E-7) which was constructed by rs6756667 and rs7589621; (4) a strong linear correlation between major alleles of rs6756667-A (R 2 = 0.997, P = 0.002), rs7589621-G (R 2 = 0.994, P = 0.003), rs1868092-A (R 2 = 0.985, P = 0.008) and altitude by linear correlation test. The associations between HIF2A variants and different level of high altitude support that extremely high-altitude hypoxia challenge imposes selective effects on HIF2A variants among native Tibetans.

Demographic History and Genetic Adaptation in the Himalayan Region Inferred from Genome-Wide SNP Genotypes of 49 Populations

“…These are rs1868092, downstream of EPAS1 in a promoter-flanking region which has previously been associated with high-altitude adaptation and shown to be a single-tissue eQTL in whole blood ( Petousi et al. 2014 ; Basang et al. 2015 ), and rs982414, an intronic variant ∼231 kb downstream of EPAS1 , which has been associated with hemoglobin concentration in Tibetans ( Beall et al.…”

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

“…Interestingly, in a study of native Tibetans residing at different HAs, the rs6756667 A allele was dominant. As the altitude increased, there was a linear decreasing trend in GG and AG carriers and an increasing trend in AA carriers [ 31 ]. Studies of Tibetans revealed that this population comprises a mixture of ancestral populations related to the Sherpa and Han Chinese [ 32 ].…”

Computational EPAS1 rSNP Analysis, Transcriptional Factor Binding Sites And High Altitude Sickness Or Adaptation

“…The allele frequencies of four EPAS1 SNPs (rs56721780, rs6756667, rs7589621 and rs1868092) significantly associated with different levels of highaltitude hypoxia among native Tibetans [20] are presented in Table 1 Table 3).…”

“…The EPAS1 gene maps to human chromosome 2p21 and is about 120 kb in size with a coding region consisting of 15 exons [19]. Four HIF2a SNPs (rs56721780, rs6756667, rs7589621 and rs1868092) have been significantly associated with different levels of high-altitude hypoxia among native Tibetans [20]. The rs56721780 SNP in the HIF2a promoter region has also been significantly associated with high-altitude adaptation of Tibetans [9] while the rs6756667 SNP from intron two has been significantly associated with susceptibility to acute mountain sickness in individuals sequences.…”