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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.

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