Johnson, L.; (2010) Genetically determined variation of respiratory mucins: disease and demography. Doctoral thesis , UCL (University College London).

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Abstract

Airway mucus protects and maintains the health of the respiratory tract. Its production is orchestrated by environmental cues, thus inter-individual variation in mucus composition, quantity and rheology is likely to confer differences in disease susceptibility and response, and may also result in environmental specific suitability. Glycoproteins known as mucins are considered to be the major components of mucus. This project is concerned with the large secreted airway mucins that are encoded by MUC5AC and MUC5B, with the overall aim being to study their genetic variation in relation to disease and demography. Using a single base extension genotyping method, this project reports for the first time, significant associations between five dependent allergy related respiratory outcomes, including asthma, and a single nucleotide polymorphism of MUC5AC in a European longitudinal cohort. The cause of these associations could not however be refined and therefore further characterisation of the MUC5AC gene is essential for understanding the relationship between allergic airways and MUC5AC. Variants of the MUC5B gene have also been explored in relation to asthma. Variation of the MUC5B upstream promoter region has been characterised in two asthmatic disease case-control cohorts by Sanger sequencing. Statistically significant associations are reported here between regulatory variants of MUC5B, whereby the ‘high’ expressing promoter haplotype is significantly underrepresented in a sample set of severe asthmatic cases as compared to their controls. To further characterise variation within these genes, the MUC5B promoter has also been sequenced in a sample set of eight African populations and the patterns of regulatory diversity have been examined in relation to population differentiation, geographic demarcation and species conservation profiles. We show here for the first time, a statistically significant overrepresentation of the ‘high’ expressing promoter haplotype in a collection of the Anuak peoples of Ethiopia as compared to four other Ethiopian sample sets of differing Ethnicity.

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