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Title: Genetics of the sleep apnoea/hypopnoea syndrome
Author: Riha, Renata Ludmilla
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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This thesis examined possible candidate genes that might contribute towards the development of OSAHS. The genes of interest included tumour necrosis factor –alpha (potential associations with ageing, hypercytokinaemia in OSAHS, obesity and sleepiness). Apolioprotein E (associations with the development of cerebrovascular disease), the serotonin receptor 2A (modulation of upper airway muscle tone and response to selective serotonin re-uptake inhibitors), beta-2 adrenoreceptor (growth, fat metabolism and blood pressure) and the growth hormone receptor (influence on postnatal bone growth and height including the craniofacial complex). 557 consecutive subjects with a diagnosis of OSAHS were approached at the Scottish Sleep Centre. 104 subjects (all Caucasian) were recruited together with 107 of their siblings as well as an additional 17 unrelated subjects without OSAHS and underwent overnight polysomnography and cephalometry. Blood was taken for DNA analysis. Subjects were classified as having definite OSAHS (n=110), indeterminate status (n=34) or not having OSAHS (n=83) based on their apnoea/hypopnoea frequency and sleepiness as measured by the Epworth Sleepiness Score. DNA was extracted using standard techniques and polymorphisms in the candidate genes were examined using allelic discrimination testing with TaqMan™. The Apolipoprotein E4 polymorphisms were determined using polymerase chain reaction, restriction fragment length polymorphism. DNA from192 random, healthy UK blood donors (assumed not to have OSAHS) was used as an additional control. Differences between subjects with and without OSAHS were as expected: there were over twice as many men in the OSAHS group compared to the non-OSAHS group (p<0.0001) and systolic blood pressure was significantly higher (p = 0.002) in the OSAHS group. Furthermore, the OSAHS group were more obese (p<0.0001) and had a greater neck circumference (p<0.0001) than the non-OSAHS group. Cephalometry revealed that both male and female apnoeics had significantly lower-set hyoid bones than non-apnoeic snorers (p = 0.01 and p = 0.038 respectively). In male subjects with OSAHS, a smaller mandible and lower-set hyoid were the most important characteristics distinguishing siblings with from sibs without OSAHS, independently of age and BMI. However, age, sex, BMI and edentulism were found to influence craniofacial parameters in both groups. For the genetic analyses, the Apo E e4 allele (examined in 73 subjects) was not associated significantly with a diagnosis of OSAHS. In addition, the TNF-a – 308 A allele showed significant association with the OSAHS phenotype when comparing siblings discordant for carriage of this allele. The increased prevalence of some of the minor polymorphisms in the study population with OSAHS suggested there may be abnormalities in metabolism and the regulation of growth, which may directly contribute to its aetiology. These preliminary findings would require exploration in other populations, but are compatible with OSAHS being a polygenic disorder. This thesis highlights that there is much to be done in our search for relevant genetic factors that will lead to a greater understanding of this complex, chronic and very common disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available