Role of Allergic Sensitization, Filaggrin Variants, and DNA Methylation on the Risk of Allergic Disorders

Background: Allergic disorders, including eczema, asthma, and rhinitis, have emerged as a global public health concern due to their elevated prevalence and the associated clinical morbidity. Environmental, immunologic, and genetic factors have been implicated in the pathogenesis of allergic disorders. Allergic sensitization (representing deviated immune responses) and filaggrin gene (FLG) variants (leading to dysfunctional epidermal barrier) have shown to be common predisposing factors in the development of allergic disorders. However, there is a lack of knowledge on their joint effects on the development of single and multiple (coexistence) allergic disorders. More recently, epigenetic mechanisms, such as DNA methylation, have emerged as potentially important factors in the development of such complex diseases; however, the extent to which DNA methylation associates with allergic disorders is unclear. Objectives: This dissertation sought to (i) determine whether eczema and/or allergic sensitization is an effect modifier of the association between ‘FLG variants and asthma’ and ‘FLG variants and rhinitis’, (ii) test whether FLG variants and allergic sensitization jointly predispose to the comorbidity of eczema, asthma and rhinitis, and (iii) examine associations between DNA methylation across the epidermal differentiation complex (EDC) genomic region with eczema status. Methods: The Isle of Wight (IOW) birth cohort, a population-based sample of 1,456 infants born between January 1989 and February 1990, was prospectively assessed at