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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.

SUBMITTER: Esparza-Gordillo J

PROVIDER: S-EPMC4355615 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.

Esparza-Gordillo Jorge J Matanovic Anja A Marenholz Ingo I Bauerfeind Anja A Rohde Klaus K Nemat Katja K Lee-Kirsch Min-Ae MA Nordenskjöld Magnus M Winge Marten C G MC Keil Thomas T Krüger Renate R Lau Susanne S Beyer Kirsten K Kalb Birgit B Niggemann Bodo B Hübner Norbert N Cordell Heather J HJ Bradley Maria M Lee Young-Ae YA

PLoS genetics 20150310 3

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 Europea ...[more]

PMID: 25757221

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Project description:Importance:Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated. Objectives:To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD. Design, Setting, and Participants:This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019. Main Outcomes and Measures:Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD. Results:A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80). Conclusions and Relevance:The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.

Project description:ImportanceSkin microbiome correlates with disease severity for lesional and nonlesional skin, indicating a global influence of atopic dermatitis (AD). A relation between skin microbiome and filaggrin gene (FLG) mutations proposes a possible association between skin microbiome and host genetics.ObjectivesTo assess skin and nasal microbiome diversity and composition in patients with AD and compare with healthy controls, and to investigate the microbiome in relation to disease severity and FLG mutations in patients with AD.Design, setting, and participantsAn observational case-control study of 45 adult healthy controls and 56 adult patients with AD was carried out from January 2015 to June 2015 in a tertiary referral center, Department of Dermatology, Bispebjerg Hospital, Denmark.ExposuresBacterial swabs were taken from patients with AD (lesional skin, nonlesional skin, and anterior nares) and from healthy controls (nonlesional skin and anterior nares). Eczema severity was assessed and FLG mutations noted. Bacterial DNA was extracted from swabs, and V3-V4 16S rDNA regions amplified with PCR. Samples were analyzed at Statens Serum Institut September 2015 to September 2016. Bioinformatics analyses of the microbiome were analyzed using R statistical software (version 3.3.1, R Foundation Inc).Main outcomes and measuresSkin microbiomes were investigated using next-generation sequencing targeting 16S ribosomal RNA.ResultsMicrobiome alpha diversity was lower in patients with AD compared with healthy controls in nonlesional skin (effect size, 0.710; 95% CI, 0.27-1.15; P = .002), lesional skin (effect size, 0.728; 95% CI, 0.35-1.33; P = .001), and nose (effect size, 1.111; 95% CI, 0.48-0.94; P < .001). Alpha diversity was inversely correlated with disease severity for lesional (effect size, 0.530; 95% CI, 0.23-1.64; P = .02) and nonlesional skin (effect size, 0.451; 95% CI, 0.04-2.44; P = .04) in patients with AD. Microbiome composition in AD nonlesional skin was linked to FLG mutations.Conclusions and relevanceAn altered microbiome composition in patients with AD in nonlesional skin, lesional skin, as well as nose, suggests a global influence of AD. Microbiome composition in AD nonlesional skin is associated with FLG mutations, proposing a possible association between the skin microbiome and host genetics.

Dataset Information

Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.

Publications

Maternal filaggrin mutations increase the risk of atopic dermatitis in children: an effect independent of mutation inheritance.

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