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Title: Acute physiological responses to normobaric hypoxic exposure in humans : potential genetic associations
Author: Hennis, Philip John
ISNI:       0000 0004 2682 952X
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2009
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During exposure to a hypoxic environment, as found at high altitude, various physiological acclimation responses occur in humans that reduce the magnitude of hypoxia at systemic, tissue, and cellular levels. Several physiological responses to hypoxia are highly variable between individuals and this influences individuals' ability to acclimatise and exercise in these conditions. A large amount of the variability in these responses can be attributed to genetic factors. However, very few studies have investigated associations between specific genetic polymorphisms and the acclimation responses to hypoxia. Therefore, it was the intention of this thesis to examine whether several physiological responses to hypoxia were influenced by 2 genetic polymorphisms; namely, the HIFIA C1772T gene which encodes the transcription factor hypoxia inducible factor-la (HIF-la), and the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism. The first study of this thesis, presented in Chapter 4, investigated the effect of 6 h hypoxic exposure on erythropoietin (EPO) production in humans. Results were compared to a normoxic control group, used to examine the purported diurnal variation in serum EPO levels. This study showed that 6 h normobaric hypoxic exposure (15.6% O2) increased serum EPO levels by 97 ± 67%, and values were significantly higher than the normoxic control (P < 0.001). The EPO increase can be attributed solely to the effect of the hypoxic exposure, as no diurnal variation in serum EPO concentration was shown in the normoxic control group. The second study, presented in Chapter 5, investigated whether the inter-individual variations in EPO and SaOz responses to hypoxia, as shown in Chapter 4, were influenced by two genetic polymorphisms. In 28 males, no association was observed between the HIFIA C1772T polymorphism and the EPO and SaO? responses during 6 h exposure to 15.5% O2 (equivalent to 2,500 meters). The ACE I/D polymorphism was not associated with EPO production during hypoxia, although, during early exposure (2 h) SaC^ was higher in ACE II homozygotes, compared to their DD counterparts (P - 0.031). Due to the influence that the HIFIA C1772T polymorphism has on other phenotypes related to hypoxia, the third experimental study, presented in Chapter 6 , reinvestigated the potential association between it and serum EPO and SaC^ levels during a greater hypoxic stimulus and in a larger population. This study investigated whether associations exist between the HIFIA polymorphism and the EPO and SaC^ responses to 8 h exposure to 12.7% O2 (equivalent to 4,000 meters elevation), in 52 males. This 8 h exposure was also used to examine whether the HIFIA genotype was associated with susceptibility to acute mountain sickness (AMS). Furthermore, 62 participants were used to examine whether the magnitude of individuals' hypoxic ventilatory response (HVR) was influenced by the HIFIA polymorphism. No association was identified between the HIFIA C1772T polymorphism and HVR or acute acclimation responses to 8 h exposure to 12.7% O2. The greater SaC^ observed in ACE II homozygotes in the second study is potentially due to the influence of ACE on ventilation during hypoxia. The final study, presented in Chapter 7, therefore, investigated the potential association between ACE I/D genotype and the magnitude of HVR. This study investigated whether the EPO response, SaOb level, and AMS susceptibility, during exposure to 12.7% O2 were influenced by ACE genotype. This study showed that the ACE II genotype was associated with a high HVR. In contrast to the study presented in Chapter 5, the ACE I/D polymorphism was not associated to Sa0 2 . In addition, the EPO response and the level of AMS were independent o f ACE genotype. The experimental studies in this thesis demonstrate that in the populations used, the HIFIA C1772T polymorphism was not associated with acute EPO, Sa0 2 , or AMS responses during hypoxia, or with the magnitude of individuals' HVR. In contrast, the ACE I/D polymorphism, while similarly not influencing EPO production or AMS susceptibility, was associated with SaO; during exposure to moderate hypoxia. Furthermore, the ACE II genotype was associated with greater resting HVR compared to the ID and DD genotypes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available