Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives

Biochem Biophys Res Commun. 2006 Mar 24;341(4):1218-24. doi: 10.1016/j.bbrc.2006.01.086. Epub 2006 Jan 30.


High-altitude natives are adapted to hypobaric hypoxia, suggestive of genetic basis of adaptation. Since endothelin-1 (ET-1) is of prime importance in high-altitude disorders in sojourners, we envisaged the role of allelic variants of ET-1 in high-altitude adaptation. Four ET-1 polymorphisms, viz., (CT)(n)-(CA)(n) repeat, -3A/-4A, G2288T, and Lys198Asn, were investigated in 426 highlanders (HLs) and 236 lowlanders (LLs). The plasma ET-1 levels, SBP and BMI were significantly lower in the HLs than those in LLs (p<0.0001). The Longer-repeats (31-45), G allele, Longer-repeats/GG, and Longer-repeats/Lys198Lys combinations were overrepresented in the HLs (p<0.0001, p=0.03, p<0.0001, and p<0.0001, respectively). The Longer-repeats, -3A/-3A, GG and Lys198Lys genotypes associated with significantly lower ET-1 levels in the HLs (p<0.0001, p=0.001, p<0.0001, and p<0.0001, respectively). Combinations of Longer-repeats with -3A/-3A, GG, and Lys198Lys genotypes, and -3A/-3A/Lys198Lys combination revealed association with lower ET-1 levels in the HLs (p<0.001). The study reports over-representation of Longer-repeats, G allele, and wild-type genotype combinations in high-altitude natives. Interaction between these alleles and association with lower ET-1 levels strengthen their association with high-altitude adaptation. Presence of such alleles in sojourners may help in acclimatization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / genetics*
  • Adult
  • Altitude Sickness / physiopathology
  • Altitude*
  • Asian Continental Ancestry Group / genetics
  • Endothelin-1 / genetics*
  • Female
  • Gene Frequency
  • Genetic Variation*
  • Genotype
  • Humans
  • Hypoxia / physiopathology*
  • India
  • Male
  • Middle Aged
  • Repetitive Sequences, Nucleic Acid / genetics


  • Endothelin-1