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

Esparza-Gordillo J, Matanovic A, Marenholz I, Bauerfeind A, Rohde K, Nemat K, Lee-Kirsch MA, Nordenskjöld M, Winge MC, Keil T, Krüger R, Lau S, Beyer K, Kalb B, Niggemann B, Hübner N, Cordell HJ, Bradley M, Lee YA - PLoS Genet. (2015)

Bottom Line: Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother.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).

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.

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.

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Related in: MedlinePlus

Frequency of FLG mutations in fathers, mothers, individuals with atopic dermatitis and controls.Allele and genotype frequencies of the combined FLG-mutations in fathers and mothers were calculated using all available parents. AD refers to the frequency in the AD-affected children including the families and the unrelated AD-cases (available only in the Central European study). Frequency in controls corresponds to population-based individuals with unknown disease status. Results of the Central and Northern European populations are shown in panels A and B, respectively.
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pgen.1005076.g001: Frequency of FLG mutations in fathers, mothers, individuals with atopic dermatitis and controls.Allele and genotype frequencies of the combined FLG-mutations in fathers and mothers were calculated using all available parents. AD refers to the frequency in the AD-affected children including the families and the unrelated AD-cases (available only in the Central European study). Frequency in controls corresponds to population-based individuals with unknown disease status. Results of the Central and Northern European populations are shown in panels A and B, respectively.

Mentions: Analysis of parental genotypes revealed a higher prevalence of FLG mutations in mothers than in fathers in both study populations (Fig. 1). This is consistent with the maternal genotype effect observed. Additionally the frequency of FLG mutations in the parental population (mothers and fathers together) was remarkably higher than in population-based controls of unknown phenotype. This is likely due to the recruitment of families with multiple affected children leading to a parental population enriched in strong genetic risk factors.


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

Esparza-Gordillo J, Matanovic A, Marenholz I, Bauerfeind A, Rohde K, Nemat K, Lee-Kirsch MA, Nordenskjöld M, Winge MC, Keil T, Krüger R, Lau S, Beyer K, Kalb B, Niggemann B, Hübner N, Cordell HJ, Bradley M, Lee YA - PLoS Genet. (2015)

Frequency of FLG mutations in fathers, mothers, individuals with atopic dermatitis and controls.Allele and genotype frequencies of the combined FLG-mutations in fathers and mothers were calculated using all available parents. AD refers to the frequency in the AD-affected children including the families and the unrelated AD-cases (available only in the Central European study). Frequency in controls corresponds to population-based individuals with unknown disease status. Results of the Central and Northern European populations are shown in panels A and B, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355615&req=5

pgen.1005076.g001: Frequency of FLG mutations in fathers, mothers, individuals with atopic dermatitis and controls.Allele and genotype frequencies of the combined FLG-mutations in fathers and mothers were calculated using all available parents. AD refers to the frequency in the AD-affected children including the families and the unrelated AD-cases (available only in the Central European study). Frequency in controls corresponds to population-based individuals with unknown disease status. Results of the Central and Northern European populations are shown in panels A and B, respectively.
Mentions: Analysis of parental genotypes revealed a higher prevalence of FLG mutations in mothers than in fathers in both study populations (Fig. 1). This is consistent with the maternal genotype effect observed. Additionally the frequency of FLG mutations in the parental population (mothers and fathers together) was remarkably higher than in population-based controls of unknown phenotype. This is likely due to the recruitment of families with multiple affected children leading to a parental population enriched in strong genetic risk factors.

Bottom Line: Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother.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).

View Article: PubMed Central - PubMed

Affiliation: Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.

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.

Show MeSH
Related in: MedlinePlus