Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance

• DOI: 10.1371/journal.pgen.1005076
• Publication Date: 2015-03-10T17:51:33Z
• Authors: Jorge Esparza-Gor...; Anja Matanovic; Ingo Marenholz; Anja Bauerfeind; Klaus Rohde; Katja Nemat; Min-Ae Lee-Kirsch; Magnus Nordenskjöld; Marten C. G. Winge; Thomas Keil; Renate Krüger; Susanne Lau; Kirsten Beyer; Birgit Kalb; Bodo Niggemann; Norbert Hübner; Heather J. Cordell; Maria Bradley; Young-Ae Lee
• Keywords: Ichthyosis vulgaris

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or maternal effects reflecting genome's influence child during prenatal development. Loss-of-function mutations in filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose atopic dermatitis (AD). We investigated 4 most prevalent European FLG (c.2282del4, p.R501X, p.R2447X, p.S3247X) two samples including 759 450 AD families. used multinomial maximum-likelihood approach implemented PREMIM/EMIM tool model parent-of-origin effects. Beyond known role inheritance (R1meta-analysis = 2.4, P 1.0 x 10−36), we observed a strong genotype was consistent both independent family sets for all analysed. Overall, children FLG-carrier mothers had 1.5-fold increased (S1 1.50, Pmeta-analysis 8.4 10−8). Our data point additive mutations: i) carrying mutation ii) having carrier mother. The seen as non-genetic transmission genetic effect. only when allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting mutation-induced systemic immune responses mother may child. Notably, reported here stronger than common factors recently identified genome-wide association (GWAS). study highlights power family-based identification new etiological mechanisms reveals, first time, direct offspring's susceptibility human disease.