title: Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.
abstract: 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 due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10-36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10-8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring's susceptibility to a common human disease.
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Matanovic
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Marenholz
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bauerfeind
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rohde
authors.affiliation: Klinik fur Kinder- und Jugendmedizin, Technical University Dresden, Dresden, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Nemat
authors.affiliation: Klinik fur Kinder- und Jugendmedizin, Technical University Dresden, Dresden, Germany.
authors.forename: Min-Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marten C G
authors.initials: MC
authors.lastname: Winge
authors.affiliation: Institute for Social Medicine, Epidemiology and Health Economics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Keil
authors.affiliation: Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Krüger
authors.affiliation: Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lau
authors.affiliation: Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Beyer
authors.affiliation: Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Kalb
authors.affiliation: Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Niggemann
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Dermatology Unit, Department of Medicine, Solna Karolinska University Hospital, Stockholm, Solna, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Bradley
authors.affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
mesh_terms: D003876:Dermatitis, Atopic / Q000235:genetics*; D005260:Female; D000091344:Filaggrin Proteins; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D009154:Mutation
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins