New insights from genetic studies of eczema

Genome-wide association studies (GWAS) provided fundamental insight into the genetic determinants of complex allergic diseases. For eczema, 58 susceptibility loci were reported. Protein-changing variants were associated with eczema at genome-wide significance at 12 loci. The majority of risk variants were, however, located in non-coding, regulatory regions of the genome. Prioritized target genes were enriched in pathways of the immune response and of epithelial barrier function. Interestingly, a large overlap in the genetic architecture underlying different allergic diseases was identified pointing to common pathomechanisms for eczema, asthma, hay fever, and food allergy. Here, we review the most recent findings from GWAS for eczema including the role of rare variants and genetic heterogeneity in ethnically diverse populations. In addition, we provide an overview of genes underlying Mendelian disorders featuring eczematous skin inflammation

Filaggrin loss-of-function mutations are associated with persistence of egg and milk allergy

BACKGROUND: A genetic defect in the epidermal barrier protein filaggrin plays a major role in the etiology of eczema and associated allergic airways diseases. However, it is still controversial to what extend loss-of-function (LOF) mutations in the filaggrin gene (FLG) contribute to the development and persistence of food allergies.OBJECTIVE: We tested association of FLG LOF mutations with allergic reactions to diverse foods and investigated their potential effect on the persistence of early food allergies. METHODS: We recruited 890 children with challenge-proven food allergy for the German Genetics of Food Allergy Study (GOFA). Longitudinal data were available for 684 children. All children were clinically characterized, including their allergic responses to specific foods, and genotyped for the four most common LOF mutations in FLG; R501X, 2282del4, R2447X, and S3247X. Associations between FLG mutations and food allergies were analyzed by logistic regression using the German Multicenter Allergy Study cohort as control population. RESULTS: FLG mutations were associated with allergies to diverse foods including hen's egg (HE), cow's milk (CM), peanut, hazelnut, fish, soy, cashew, walnut, and sesame with similar risk estimates. Effects remained significant after adjusting for the eczema status. Interestingly, FLG mutations increased the risk of a persistent course of HE and CM allergy. CONCLUSION: Using the gold standard for food allergy diagnosis, we demonstrate that FLG LOF mutations confer a risk of any food allergy independent of eczema. They predispose to the persistence of HE and CM allergy and should be considered in the assessment of tolerance development