Genetic studies of candidate genes in eczema

Abstract

Eczema is a common inflammatory skin disorder characterised by itching and relapsing eczematous lesions. It usually presents in early childhood and affects about 10-20% of all children. The background is multifactorial, with both environmental risk factors and hereditary factors contributing to the development of the disease. The aim with this thesis was to identify susceptibility genes that contribute to eczema development.

In a systematic analysis of global gene-expression patterns in eczema skin, we found the SOCS3 gene to be significantly more highly expressed than in skin from healthy controls and immunohistochemical analysis confirmed an elevation of the SOCS3 protein. Furthermore, we found a genetic association between eczema and a haplotype in the SOCS3 gene in two independent groups of patients (p<0.02 and p<0.03). These results strongly suggest that SOCS3, located in a chromosomal region previously linked to the disease (17q25), is a susceptibility gene for eczema.

Recent studies have identified two loss-of-function variants, R501X and 2282del4, in the filaggrin (FLG) gene as predisposing factors for eczema. To determine the frequency of these variants and test for association we analysed transmission in 406 multiplex eczema families. In accordance with previous studies we found association between the filaggrin gene variants and atopic eczema (p<1×10 7). The highest odds ratio for the combined allele was found for the subgroup with a severe eczema phenotype (OR 4.73 (1.98 11.29), p<4×10 8). Association was also found with raised total serum IgE, allergic asthma, and allergic rhinoconjunctivitis occurring in the context of eczema. Our results support an important role for the filaggrin gene variants R501X and 2282del4 in the development and severity of atopic eczema.

In order to identify new molecular disease determinants of eczema, we analysed differentially expressed genes in a mouse model with an eczema-like phenotype. CRNN was identified and altered gene expression was confirmed with Real Time PCR. The CRNN gene was then further investigated by genetic association analysis. We found association with atopic eczema, but the observed association is likely to be explained by linkage disequilibrium between the CRNN gene and the FLG 2282del4 mutation. Therefore, the role of CRNN in eczema needs to be further evaluated.

Lack of genetic association between eczema and the asthma susceptibility gene NPSR1 was found when analysing seven polymorphisms in the gene in five European patient materials. Expression of NPSR1 in the epidermis showed no apparent difference between eczema patients and healthy controls. In addition there was no association with asthma, elevated IgE, or atopic sensitisation in the context of eczema. In summary, the SOCS3 gene has been identified as a potential novel susceptibility gene for eczema. Furthermore, the FLG gene has been confirmed as an important susceptibility gene for eczema and a marker of disease severity. Finally, the CRNN gene has been identified as a differentially expressed gene in eczema skin.