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 SEATON cohort comprising 2000 pregnant women recruited 1997-99 was established to test if maternal nutrition during pregnancy affects the likelihood of children developing asthma. At 32 weeks gestation mothers’ diets were assessed by food frequency questionnaire. 1,924 live singleton births comprised the birth cohort with follow-up at 6 months, 1, 2, 5 and 10 years (the latter the focus of this thesis). Children’s diets were assessed at 5 and 10 years. Their asthmatic status was assessed by International Study of Asthma and Allergies in Childhood questionnaire. Children participating at 5 or 10 years were also invited for measurement of spirometry and allergy. Cross-sectionally at 10 years 934 children (48% boys) participated by return of questionnaire, 449 also took part in the in-depth assessment. Higher maternal vitamin D intakes were associated with decreased odds of ‘doctor diagnosed asthma’, ‘wheeze ever’ and ‘wheeze in the last year’ in the children. Contrary to findings at 5 years no association between maternal vitamin E intake and asthma outcomes was seen. Longitudinally over the 10 years of the study, higher maternal vitamin D and E intakes during pregnancy were both associated with a decreased likelihood of ‘doctor diagnosed asthma’, ‘active asthma’ and ‘wheeze in the last year’ in the children. In conclusion, reduced maternal vitamin D and E intakes during pregnancy are associated with an increased likelihood of childhood asthma during the first ten years of life. Vitamin E appears to be associated with early asthma and wheeze possibly reflecting a role in affecting early airway remodelling processes. Associations with vitamin D were seen consistently over different time-points, possibly having its effect in an immunomodulatory fashion. Intervention trials are required to ascertain if intervention during pregnancy actually reduces childhood asthma rates.