Finemapping of susceptibility loci for atopic dermatitis on chromosome 1q21.3 and chromosome 11q13.5

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Atopic eczema (AE) and psoriasis are two common inflammatory skin diseases which are multifactorial and complex in their presentation, progression, and outcome. They are influenced by the interaction of multiple genetic and environmental factors, making it challenging to identify genetic components responsible for the cause, severity, and progression. Interestingly, although clinically and pathologically AE and psoriasis are quite different, genetic linkage studies indicate an overlap of several susceptibility loci. One such shared locus is located on chromosome 1q21.3 overlying the epidermal differentiation complex (EDC), which is cluster of genes encoding molecules found in the uppermost layers of the differentiating epidermis. With filaggrin (FLG) a strong EDC susceptibility gene for AE has recently been identified. However, FLG mutations account only partially for the genetic linkage of AE to the EDC, and show a reduced penetrance of approximately 40%. Accordingly, in a large genome-wide association study (GWAS) for AE we obtained evidence for additional risk variants within the EDC. Concerning psoriasis, so far the susceptibility variant responsible for the linkage signal to 1q21.3 has not been identified, but a recent GWAS confirms presence of a psoriasis locus within the EDC. Thus, there might be EDC genes exhibiting distinct classes of mutations which predispose to either AE or psoriasis. Alternatively there might be polymorphisms in two or more physically close and genetically similar genes, encoding functionally related but nevertheless distinct molecules, which might give rise to either psoriasis or AE.Based on previous investigations and current genome-wide data the current proposal aims at further fine-mapping and molecular characterization of genes within the EDC and their role for AE and psoriasis.