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

PLoS One. 2015 Sep 14;10(9):e0137956. doi: 10.1371/journal.pone.0137956. eCollection 2015.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Altitude Sickness / ethnology
  • Altitude Sickness / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Humans
  • Hypoxia / ethnology
  • Hypoxia / genetics*
  • Polymorphism, Single Nucleotide*
  • Selection, Genetic*
  • Tibet / ethnology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • endothelial PAS domain-containing protein 1

Grants and funding

This research was supported by grants from, the National Natural Science Foundation of China (no. 31330038, 30760274, 81060161, http://www.nsfc.gov.cn/), and grant from the National Basic Research Program (2012CB944600, http://www.973.gov.cn/), and grants from Shanghai Western Cooperation Project (no. 11495801700, http://www.stcsm.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.