Abstract
Atopic dermatitis (AD) is a complex multifactorial inflammatory skin disease that affects ~280 million people worldwide. About 85% of AD cases begin in childhood, a significant portion of which can persist into adulthood. Moreover, a typical progression of children with AD to food allergy, asthma or allergic rhinitis has been reported (“allergic march” or “atopic march”). AD comprises highly heterogeneous sub-phenotypes/endotypes resulting from complex interplay between intrinsic and extrinsic factors, such as environmental stimuli, and genetic factors regulating cutaneous functions (impaired barrier function, epidermal lipid, and protease abnormalities), immune functions and the microbiome. Though the roles of high-throughput “omics” integrations in defining endotypes are recognized, current analyses are primarily based on individual omics data and using binary clinical outcomes. Although individual omics analysis, such as genome-wide association studies (GWAS), can effectively map variants correlated with AD, the majority of the heritability and the functional relevance of discovered variants are not explained or known by the identified variants. The limited success of singular approaches underscores the need for holistic and integrated approaches to investigate complex phenotypes using trans-omics data integration strategies. Integrating omics layers (e.g., genome, epigenome, transcriptome, proteome, metabolome, lipidome, exposome, microbiome), which often have complementary and synergistic effects, might provide the opportunity to capture the flow of information underlying AD disease manifestation. Overlapping genes/candidates derived from multiple omics types include FLG, SPINK5, S100A8, and SERPINB3 in AD pathogenesis. Overlapping pathways include macrophage, endothelial cell and fibroblast activation pathways, in addition to well-known Th1/Th2 and NFkB activation pathways. Interestingly, there was more multi-omics overlap at the pathway level than gene level. Further analysis of multi-omics overlap at the tissue level showed that among 30 tissue types from the GTEx database, skin and esophagus were significantly enriched, indicating the biological interconnection between AD and food allergy. The present work explores multi-omics integration and provides new biological insights to better define the biological basis of AD etiology and confirm previously reported AD genes/pathways. In this context, we also discuss opportunities and challenges introduced by “big omics data” and their integration.
Highlights
Atopic dermatitis (AD) is an inflammatory potentially debilitating skin disease associated with itch and eczematous lesions
Using multi-omics analysis, we showed that previously suspected genes, such as FLG and SERPINB3, were associated with AD among multiple omics types
Macrophage, endothelial cell/ endothelin 1 (ET-1), Th1/Th2, NFκB, and fibroblast activation pathways were overrepresented in AD from multiple omics level results
Summary
Atopic dermatitis (AD) is an inflammatory potentially debilitating skin disease associated with itch and eczematous lesions. Investigators have used different “omics” tools (e.g., genomics, epigenomics, transcriptomics, proteomics) to study complex disease conditions like AD and generate potential omics candidates (e.g., candidate genes, transcripts, proteins, lipid mediators).
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