Associate editor: R.M. Wadsworth
The genetic basis of high-altitude pulmonary oedema

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Abstract

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 [AT1]-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.

Introduction

High-altitude pulmonary oedema (HAPE) is a potentially fatal condition, which normally occurs at altitudes in excess of 3000 m and affects fit and previously well individuals (Peacock, 1995). Hypoxia, cold, and exertion are the main predisposing factors to the development of HAPE. However, the precise pathoaetiology remains unknown and there is no reliable method for predicting those who might fall ill. Classically, the affected individual will have travelled rapidly to altitude and have undertaken strenuous exercise. Symptoms of mild-altitude sickness (headache, nausea, and sleep disturbance) onset usually between the 2nd and the 4th days at altitude and may or may not precede the development of HAPE, which can present as excessive dyspnoea, lethargy, and, in some cases, chest pain. A dry cough is common and precedes the development of respiratory crackles. Tachycardia and mild pyrexia frequently occur together with white frothy sputum, which eventually becomes blood stained. In a matter of hours, the dyspnoea worsens and respiratory failure sets in, leading eventually to death. Chest radiographs demonstrate prominent pulmonary arteries and irregular patchy infiltrates in both lung fields, which sometimes favour the dependent side. Current treatment involves administration of oxygen and nifedipine but, in particular, return to lower altitude (Basnyat & Murdoch, 2003).

Those who have suffered HAPE run a significant but unpredictable risk of recurrence, and this is one feature that suggests a constitutional, and possibly a genetic, component in its aetiology. Advances in the understanding of the biochemical pathways involved in the physiological response to hypoxia have led to greater insights into the pathogenesis of HAPE. It has become apparent that the genes encoding the mediators of these pathways are influenced by hypoxia. Polymorphisms within these genes may explain the individual variation in hypoxic responses and perhaps indicate susceptibility to high-altitude disease. Alternatively, there may be other genes involved in the pathogenesis of HAPE that apparently are unrelated to hypoxic adaptation. The physiological mechanisms of these are not well defined but are associated with an observable beneficial or damaging phenotype. An example of this is the insertion (I) genotype for the angiotensin-1 (AT1)-converting enzyme (ACE) on chromosome 17q23, which has been associated with enhanced performance at altitude and may provide a marker for differentiating altitude response (Woods et al., 2000). The first part of this review will describe the pathophysiology and the relevant mediator systems that are involved in the development of HAPE. The second part will review the genetic basis to these mediator systems and the role of the ACE genotype in altitude performance and illness.

Section snippets

Hypoxic pulmonary vasoconstriction

The pulmonary oedema of HAPE is characteristically rich in protein and occurs with a normal left atrial pressure; the most striking feature of HAPE is the grossly elevated pulmonary artery pressure (PAP) seen in those affected Penazola & Sime, 1969, Roy et al., 1969, Hultgren & Marticorena, 1978. The hypoxic pulmonary vascular response (HPVR) is a vestigial reflex from in utero life where it aids the shunting of blood away from the fetal lungs. In adult life, the same response facilitates the

Susceptibility to high-altitude pulmonary oedema

The incidence of HAPE is thought to be in the region of 0.1–0.4% of those travelling to altitudes in excess of 2500 m, but predicting those likely to develop HAPE is difficult (Basnyat & Murdoch, 2003). However, certain physiological phenotypes have been linked to HAPE susceptibility. The genes responsible for these phenotypes may prove to be crucial in understanding the genetics of HAPE and identifying those at risk.

Elevated pulmonary vascular pressor responses are seen in individuals without

Biochemical mediators of high-altitude pulmonary oedema

Both systemic and local mediators influence pulmonary vascular tone. Sympathetic activation and adrenal catecholamines have been implicated in the pathogenesis of HAPE and fluid balance is thought to be a contributory factor. However, what has become apparent is the central role of the endothelium in mediating the vascular responses to hypoxia.

The genetics of the hypoxic response: hypoxia response elements and hypoxia-inducible factor-1

HAPE occurs following exposure to hypobaric hypoxia in otherwise normal individuals. As yet, no gene for HAPE has been identified; therefore, it may be helpful to examine genes that are responsive to hypoxia to see if an understanding of their responses under these conditions may point toward a genetic basis for this syndrome.

A physiological approach to the genetics of high-altitude pulmonary oedema and high-altitude performance: Angiotensin-1-converting enzyme gene polymorphisms and altitude

The association of high-altitude illness or enhanced performance at altitude with a particular genetic polymorphism is another approach to identifying the genetics underlying the development of HAPE. Genetic polymorphisms are subtle variations in a gene, which produce minor changes in function. Under normal circumstances, these might pass unnoticed with no observable effect, but changes in environment may elicit an unexpected phenotype, which may prove beneficial or disadvantageous.

There is no

Summary

The genetic basis underlying the development of HAPE remains unknown, although there are several candidate genes. In addition, it is evident that there are molecular mechanisms for sensing hypoxia and that these can directly affect the expression of certain genes, some of which could be involved in the pathogenesis of HAPE. Polymorphisms in these genes provide a possible mechanism by which we could account for interindividual variability in response to hypoxia and hence explain both the

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