Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497874
Title: Cis-acting polymorphism of MUC gene expression
Author: Loh, Andrew Xiong Wen
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Abstract:
Mucins are high molecular weight glycoproteins that are the principal protein components of mucus and are found on epithelial surfaces throughout the body, where they play a protective role. Changes in mucin expression have been demonstrated in various diseases, such as asthma and COPD and in the respiratory system, overproduction of mucus can cause blockage of the airways. Experimental studies show co-ordinated upregulation of both mRNA and mucin protein in response to inflammation. Recent work suggests that allelic differences in gene expression are a common occurrence in the genome. The major research question addressed in this thesis is whether the MUC genes exhibit this phenomenon and if such allelic differences in expression might contribute to an individual's susceptibility to disease. Two mucins, MUC4 (membrane-bound) and MUC5B (secreted) were examined, and their relative allelic transcript levels studied by a single-base extension (SBE) method and related to haplotypes of the two genes. The first aim for MUC4 was to explore the possible influence of tandem repeat length on mRNA expression. However it was discovered that MUC4 alternative splicing is much more extensive than previously reported, with hints that this might be genetically determined, but making the original question unanswerable. The remainder of the thesis foccussed on MUC5B. For the expression studies, a total of 42 heterozygous samples were tested by SBE, of which 10 showed strong evidence of an allelic difference in MUC5B expression. These constitutive differences were small (greatest difference about two-fold). However, a highly significant association between MUC5B promoter haplotype heterozygosity and the magnitude of the detected allelic differences in MUC5B expression was demonstrated. A high expressing haplotype was identified (HI) and carriers of marker alleles for this haplotype were tested in a longitudinal birth cohort (n=2807) to examine this variation in relation to respiratory outcomes (eg. asthma), as well as to measures of lung function. Significant correlations were detected between MUC5B and allergy and wheeze history, although the significance of these correlations is unclear and could reflect differences in MUC5B properties rather than expression, or might have arisen from multiple testing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.497874  DOI: Not available
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