SUNBEAM Birth Cohort: Deciphering the role of early life skin dysfunction in development of the allergic march - PROJECT SUMMARY/ABSTRACT Allergic diseases, including atopic dermatitis (AD), food allergies (FA), and asthma are common in young children and are often co-morbid, suggesting a shared allergic pathobiology. Supporting this, development of these diseases often occurs in a sequential pattern across infancy known as the “allergic march,” with a diagnosis of AD before 12-months resulting in increased risk of FA and asthma. However, only a subset of infants with AD proceed down the allergic march for unknown reasons. We hypothesize that different pathobiological mechanisms (i.e. endotypes) operating in the skin, underlie AD clinical subtypes and their propensity to give rise to additional allergic diseases. Supporting this, we have found a type 2 inflammatory skin endotype that was greatly increased in AD subjects with FA relative to AD subjects without FA, with the ADFA+ patients also exhibiting skin barrier abnormalities. Moreover, animal models have shown that skin barrier disruption with inflammation can drive sensitization to allergens and the development of AD, FA, and airway inflammation. Genetic studies also support a shared genetic disposition among allergic diseases and implicate dysregulation of skin genes in this risk. Among adults, heterogeneity in inflammatory skin endotype has been observed, including Th22, Th17, IL36G, and Th1 pathway activation. The roles of these endotypes in progression of infants through the allergic march is unexplored. We have pioneered skin tape stripping (STS) RNA-seq methods to allow repeated, minimally invasive skin expression profiling. Using these methods, we will evaluate whether early-life skin pathobiology leads to the development of the allergic march and other sequences of allergic disease development. Our proposal relies on phenotyping and STS samples collected in the Systems Biology of Early Atopy (SUNBEAM) birth cohort (n=2500). From a SUNBEAM allergic disease case-cohort (n~800) we will generate RNA-seq data on STS samples collected at birth, 2, 5, 12, 24, and 36 months, paired with allergic disease phenotyping. In Aim 1 we will determine inflammatory endotypes of AD in infancy and their associated patterns of gene expression dysregulation. Cellular deconvolution of RNA-seq will identify immune cell types and changes in epidermal cellular composition that underlie different AD endotypes. We will determine whether skin expression and endotypes, at birth and with AD at 2 and 5 mos, are predictive of food allergy at one year of age. In Aim 2 we will determine longitudinal patterns of early life skin pathobiology that underlie the allergic march and other sequences of allergic disease development. We will define allergic disease developmental classes, their associated longitudinal expression and cellular composition profiles, and prospective biomarkers for allergic disease development. In Aim 3, whole genome- and RNA-seq data will be used to identify eQTLs that influence skin expression at each timepoint and longitudinal skin development among allergic disease groups. Using TWAS, genetic models of early-life skin gene expression will be used with GWAS data for allergic diseases to identify genetic variants influencing allergic disease risk through modulation of early-life skin gene expression.
