The genetic basis of high-altitude pulmonary oedema

Pharmacol Ther. 2004 Feb;101(2):183-92. doi: 10.1016/j.pharmthera.2003.11.003.


High-altitude pulmonary oedema (HAPE) is a potentially fatal condition affecting fit and previously well individuals at altitudes in excess of 3000 m. This article discusses the mechanisms of HAPE, considers the contribution of hypoxic pulmonary vasoconstriction and alterations in sodium transport to the pathological process. It discusses the various biochemical mediators such as nitric oxide (NO), endothelin-1 (ET-1), and the renin-angiotensin-aldosterone system (RAS) that may be involved and considers possible oxygen-sensing mechanisms involved in hypoxic adaptation such as hypoxia-inducible factor-1 (HIF-1). Those who have had HAPE once run an unpredictable but significant risk of recurrence; therefore, there may be a constitutional or genetic component in its aetiology. This paper considers the possible involvement of genes that may be involved in physiological adaptation to hypoxia (e.g., angiotensin-1 [AT(1)]-converting enzyme [ACE], tyrosine hydroxylase, serotonin transporter [5-HTT], and endothelial NO synthase [eNOS] genes). As yet, no formal association has been identified between an identified genetic polymorphism and HAPE, but genetic variation provides a possible mechanism to explain interindividual variation in response to hypoxia and enhanced or reduced performance at altitude.

Publication types

  • Review

MeSH terms

  • Altitude Sickness / complications
  • Altitude Sickness / genetics*
  • Animals
  • DNA-Binding Proteins / metabolism
  • Erythropoietin / genetics
  • Erythropoietin / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nuclear Proteins / metabolism
  • Polymorphism, Genetic
  • Pulmonary Edema / etiology
  • Pulmonary Edema / genetics*
  • Pulmonary Edema / metabolism
  • Renin-Angiotensin System / genetics
  • Renin-Angiotensin System / physiology
  • Transcription Factors*


  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • Erythropoietin
  • Nitric Oxide
  • Nitric Oxide Synthase