Genomic and phenotypic characterization of endotypes in atopic dermatitis

ABTRACTO_ST_ABSBackgroundC_ST_ABSAtopic dermatitis (AD) is a heritable and heterogeneous inflammatory chronic skin disorder. Utilizing decision tree/supervised learning of extensive clinical, molecular and genetic data, we aimed to define distinct AD endotypes. MethodsDeep phenotyping and whole-genome sequencing was performed on samples obtained from participants of EPIONE, a randomized-controlled phase III study in AD patients with severe pruritus comprising mild (23%), moderate (64%) and severe (13%) AD as determined by AD Investigator Global Assessment scale. Three categories of analysis were performed: clinical associations, lab value associations (EOS, IgE, cytokines) and genetic analysis of whole-genome sequencing data ResultsBased on a decision tree, we found that five clinical features from the SCORing Atopic Dermatitis (SCORAD) Index can accurately differentiate between IGA severities. We observe a significant difference between severity and eosinophil counts (p<0.001), IgE (p<0.001) and Filaggrin (FLG) LOF frequency (OR 2.3, CI 1.6-3.2, p<0.0001) as well as interleukin pathway genes, specifically IL5RA variants differentiating the groups. ConclusionOur results suggest significant differences between severity groups across a number of features appear to constitute distinct endotypes with likely distinct causative factors. Differing underlying pathophysiologys indicate endotype knowledge is critical to help guide therapeutic approaches to AD. Capsule summaryO_LIAD is a heritable and heterogeneous skin disorder that makes the one size fits all therapeutic approach suboptimal for patients with AD. C_LIO_LIWe attempted to define AD endotypes based on clinical, molecular, and genetic characteristics. Clinical, CBC, and genetic associations all tend to suggest existence of separate endotypes. C_LI