Genetics of epithelial genes in childhood asthma

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Allergic disorders are a major global health burden affecting up to 40% of the world population. Common biologic pathways underlie allergic diseases such as asthma, AD, FA and EE with the epithelium being a link. Indeed, epithelial cells are increasingly recognized as critical participants in the pathogenesis of allergic inflammation. As such, studies are needed to further elucidate the epithelial genes and pathways that contribute to allergic inflammation. This is underscored by the fact that there is currently no asthma therapy that specifically targets the epithelium. In the last cycle of funding, we utilized a novel unbiased strategy, which combined expression profiling of nasal epithelial cells from patients with asthma, population differences in asthma prevalence, and genetic association studies, to identify epithelial genes that contributed to childhood asthma. We identified several epithelial genes with previously unrecognized roles in asthma. Further analyses of these genes suggest that some of these genes are specific to one epithelial surface and are associated with one allergic disease, while others are common to multiple epithelial surfaces and allergic disorders. Collectively, our data suggest that depending on the target organ/mucosal surface, there are common and distinct epithelial genes and pathways that contribute to allergic inflammation. The Identification of the epithelial genes and pathways, which predispose individuals to specific or shared allergic disorders, will empower the search for novel therapeutics aimed specifically at the epithelial surface, and the development of treatment strategies that are optimized for allergic disorders alone and/or in combination. In the prior cycle, we studied children with asthma and/or AR. In this application, we propose to extend our genetic approach to test the hypothesis that allergy-driven epithelial genes Identified in the prior cycle of funding (SERPINB3/4, KIF3A, DNAH5, SPRR2B, ADCY2, PDE4B, PLAU, EGFR) will demonstrate unique and overlapping associations with asthma, atopic dermatitis, and/or food allergy in children and that the genetic contribution of these genes is modified by epistatic interactions with epithelial genes critical in maintaining the integrity of the mucosal barrier and/or promoting Th2 responses.