title: 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 (R2 = 0.997, P = 0.002), rs7589621-G (R2 = 0.994, P = 0.003), rs1868092-A (R2 = 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.
authors.affiliation: Medical College of Tibet University, Tibet Autonomous Region 850002, China.
authors.forename: Zhuoma
authors.initials: Z
authors.lastname: Basang
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Boyang
authors.initials: B
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Medical College of Tibet University, Tibet Autonomous Region 850002, China.
authors.forename: La
authors.initials: L
authors.lastname: Yang
authors.affiliation: Medical College of Tibet University, Tibet Autonomous Region 850002, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Medical College of Tibet University, Tibet Autonomous Region 850002, China.
authors.forename: Chaoying
authors.initials: C
authors.lastname: Cui
authors.affiliation: Medical College of Tibet University, Tibet Autonomous Region 850002, China.
authors.forename: Gongga
authors.initials: G
authors.lastname: Lanzi
authors.affiliation: People's Hospital of Tibet Autonomous Region, Tibet Autonomous Region 850000, China.
authors.forename: Nima
authors.initials: N
authors.lastname: Yuzhen
authors.affiliation: Shigatse Center for Disease Control, Tibet Autonomous Region 857000, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Duo
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Zheng
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shuhua
authors.initials: S
authors.lastname: Xu
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000532:Altitude Sickness / Q000208:ethnology / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D018609:Tibet / Q000208:ethnology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1