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Background: Asthma affects approximately 300 million people worldwide ', 5.2 million of these people live in the UK2, 1.1 million of these are children" Asthma is one of the most common chronic diseases and is the fourth leading cause of morbidity worldwide, and there is no indication of a decline in prevalence. It is hypothesised that a range of gene- environmental interactions may influence the susceptibility, severity and medication response of asthma in children and young adults". Methods: To explore these issues, two studies have been established to create datasets that will describe the phenotypic and genotypic characteristics of children with asthma in the paediatric population across Sussex and Scotland. This thesis is the output of doctoral research using data from these studies (BREATHE and PAGES) that aims to explore the interactions between variants of six genes implicated in airway remodelling and relevant environmental factors and their influence on the severity of asthma in children and young adults. This thesis is divided by analysis of individual variants. The thesis included one variant of Chitinase 3-Like-1, two variants of Matrix metalloproteinase 9, two variants of Matrix metalloproteinase 12, one variant of Matrix metalloproteinase 9, one variant of Glutathione S-tronsferase mu-1, one variant of Glutathione S-transferase theta-1 and one variant of Glutathione S-transferase pi-1. A total of eight variants were investigated. Variants were analysed for effect on multiple proxy measures of asthma severity, including asthma exacerbations, asthma treatment steps, pulmonary function and quality of life. Variants were also analysed for their effect on allergy.

The aims of this study were to describe asthma medication prescribing patterns for children in a Scottish primary care setting and to evaluate the use of routinely acquired healthcare datasets in assessing the clinical effectiveness of therapy, patient adherence with prescribed medications, and prescriber adherence with asthma treatment guidelines in the paediatric population.

Goblet cell hyperplasia (GCH) and decreased ciliogenesis are characteristic features which may be influenced by Th2 cytokines (eg IL-9 and IL-13). Studies have suggested nasal epithelium can be used as a surrogate for bronchial epithelial. AIM In vitro basal mucociliary differentiation and differences in paediatric epithelial cells (normal & asthmatics) exposed to IL-9 and IL-13 were studied. To study the feasibility of nasal epithelium as a replacement for bronchus. METHOD Bronchial (PBECs) and paired nasal brushings (PNECs) obtained from children were differentiated at air liquid interface for 28 days. Cells treated with IL-13, IL-9 or a combination of IL-9/-13. Transeplthelial resistance (TEER), number of ciliated and goblet cells, MUC5AC mRNA expression and relative absorbance of MUC5AC were assessed as a measure of tissue differentiation. RESULTS Asthmatic PBECs (PBEC(A)) had a significant GCH and fewer ciliated cells compared to normal PBEC, (PBEC(N) under un-stimulated conditions. Stimulation with 20ng/ml IL-13 in PBEC(N) and PBEC(A) resulted in GCH and decreased ciliated cell number compared to un-stimulated respective cultures. Similar was also observed in the increase of MUC5AC mRNA expression with 20ng/ml IL-13 in PBEC(A) and PBEC(N). IL-9 alone did not alter goblet cell numbers, however PBEC(N) with the IL-9/IL-13 increased goblet cell number compared with un-stimulated. IL-9 and IL-9/IL-13 stimulated PBEC(N) had reduced ciliated cell numbers compared with un-stimulated. In PBEC(A), only 20ng/ml IL-13 significantly reduced ciliated cell number compared with un-stimulated. Morphological differences observed between asthmatic and normal PNECs and PBECs was also supported by varied cytokine release and functional differences following IL-13 stimulation. CONCLUSION Morphological differences exist between normal and asthmatic PBECs and PNECs under un-stimulated conditions. IL-13 drives PBEC(N) towards an asthmatic phenotype and worsens the phenotype in PBEC(A) with reduced ciliated cell numbers and increased GCH. IL-9 alone did not stimulate GCH in PBEC(N), and showed no synergistic effect with IL-13 in driving GCH. IL-9 and IL-9/13 lowered the number of ciliated cells in PBEC(N), however this was not seen in asthmatic cells. Functional differences exist between PBEC and PNEC therefore questions the suitability of nasal epithelium as a surrogate.

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