| Summary: | The hypoxia of high altitude (‘hypobaric hypoxia’) presents a profound physiological challenge to the human body and at extreme high altitude the human body nears the limits of its tolerance for oxygen deprivation. Physical performance in this environment is limited by two major physiological elements: ‘acclimatisation’ to hypobaric hypoxia sufficient to allow strenuous physical exertion, and the avoidance of Acute High Altitude Illnesses (AHAI). The rate and effectiveness of acclimatisation and the susceptibility to AHAI varies markedly between individuals, suggesting a possible genetic influence on high altitude performance. A polymorphism of the human Angiotensin Converting Enzyme (ACE) gene has been identified in which the deletion (D-allele), rather than the insertion (I-allele), of a 287 base pair sequence is associated with higher circulating and tissue ACE activity. This polymorphism has also been associated with physical performance phenotypes, the ACE I-allele being associated with elite endurance performance. An excess frequency of the ACE I-allele has also been identified in a small sample of elite UK high altitude mountaineers. This thesis set out to test the hypothesis that the ACE I-allele is indeed associated with successful physical performance at high altitude, and to explore the mechanism by which such an advantage may be mediated. I conducted a series of prospective geneenvironment interaction studies to assess whether the ACE I-allele is associated with successful ascent to high altitude and, if such an advantage exists, whether this is mediated by reduced susceptibility to Acute Mountain Sickness (AMS) or improved oxygen saturations. To further define the underlying mechanism, I explored the association of bradykinin 2 receptor genotype with high altitude performance to investigate whether the ACE I allele contribution is mediated by increased kinin activity. Additionally I extended these observations to those who have faced the most extreme hypoxic challenge - a successful ascent of Mount Everest.
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