Human and mouse genetics studies of filaggrin-related proteins in eczema and allergy (360G-Wellcome-092530_Z_10_Z)

Our recent work has demonstrated that common loss of function variants in the filaggrin gene are the major predisposing factor in atopic eczema and related allergic diseases. Here, our overarching research goal is to extend this work to determine the role the filaggrin family of proteins in atopic disease, using human and mouse genetics, to uncover further atopy genes. Specifically, we will analyse the filaggrin gene in a number of human ancestral groups to identify ethno-specific mutatio ns linked to atopic disease. We will identify further atopy susceptibility genes in the filaggrin gene cluster using high-density SNP genotyping, copy number analysis and sequencing strategies. We will determine the genetic defect in the matted mouse mutant, which maps to the murine filaggrin gene cluster and which has an atopic phenotype. This will inform and direct our human genetics studies. We have shown that the atopic phenotype in filaggrin deficient mice is highly strain depen dent. We will use this unique resource to identify modifier loci and mouse and relate these to human disease by backcross mapping and eQTL analysis.