AbstractAtopic eczema is a common, complex trait that is highly heritable. This thesis describes a body of research over 5 years, from 2014 to 2019, highlighting six key publications. These are described on a background of intense activity within the fieldof atopic eczema genetic research, stimulated by the discovery, in 2006, of loss-of-function mutations in the gene encoding filaggrin (FLG). FLG null mutations play a major role in eczema and other atopic diseases and my work has built on this seminal discovery. I described, for the first time, transcriptomic features of FLG haploinsufficiency (Cole et al. J Allergy Clin Immunol 2014). I tested the effect ofFLG null mutations on the skin’s response to ultraviolet-induced erythema in vivo(Forbes et al. J Allergy Clin Immunol 2016). I optimised a well-established organoid model, using primary human keratinocytes and fibroblasts to recapitulate aspects of human skin for functional testing of specific genetic effects. Quantitative global proteomic analysis of the organoid model with FLG knockdown has replicated findings from previous transcriptome analyses and showed evidence of keratinocyte-immune cell cross-talk and disordered axon guidance (Elias et al. Wellcome Open Research 2019). Detailed analysis of the organoid model with knockdown of thetranscriptional repressor EMSY has shown, for the first time, that this protein is a master-regulator of multiple aspects of skin barrier formation (Elias et al. J Allergy Clin Immunol 2019). Taking a statistical approach driven by a clinical question, longitudinal latent class analysis applied to two independent populations identified distinct subgroups of eczema (Paternoster et al. J Allergy Clin Immunol 2018) in which the most long-lasting phenotypes show the greatest genetic risk, including FLG null genotype. Finally, leveraging the similarities and differences between eczema and psoriasis, a genome-wide comparative analysis identified opposing genetic mechanisms in these common inflammatory skin diseases (Baurecht et al. Am J Hum Genet 2015) providing a theoretical rationale for therapies designed to rebalance the skin’s tendency to atopic versus psoriatic inflammation. Together this body of work has substantially increased understanding of genetic mechanisms in atopic skin, with important clinical applications and opportunities for much-needed therapeutic development.
|Date of Award||2020|
|Supervisor||Frances Fuller-Pace (Supervisor) & John Hayes (Supervisor)|
Molecular and Genetic Mechanisms in Atopic Eczema
Brown, S. J. (Author). 2020
Student thesis: Doctoral Thesis › Doctor of Philosophy