Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march

• Published in: Journal of allergy and clinical immunology Vol. 118; no. 4; pp. 866 - 871
• Main Authors: Marenholz, Ingo, Nickel, Renate, Rüschendorf, Franz, Schulz, Florian, Esparza-Gordillo, Jorge, Kerscher, Tamara, Grüber, Christoph, Lau, Susanne, Worm, Margitta, Keil, Thomas, Kurek, Michael, Zaluga, Elisabetha, Wahn, Ulrich, Lee, Young-Ae
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.10.2006; Elsevier; Elsevier Limited
• Subjects: Age; Allergic diseases; allergic rhinitis; Allergies; Asthma; Asthma - complications; Asthma - genetics; atopic march; atopy; Biological and medical sciences; Child; Children & youth; Disease; Eczema; Eczema - complications; Eczema - genetics; Families & family life; Family; Family medical history; Female; filaggrin; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genes; genetic association; Genetic Predisposition to Disease; Genotype & phenotype; Heterozygote; Humans; Hypersensitivity, Immediate - complications; Hypersensitivity, Immediate - genetics; Immunopathology; Intermediate Filament Proteins - genetics; Male; Medical sciences; Mutation; Pedigree; Phenotype; Polymerase Chain Reaction; Risk Factors; Skin; Skin allergic diseases. Stinging insect allergies; skin barrier; FLG; PARF; skin barrier; OR; TDT; atopy; genetic association; asthma; GENUFAD; Eczema; atopic march; allergic rhinitis; filaggrin; MAS; skin harrier; Immunopathology; Lung disease; Allergy; Nose disease; Skin disease; Rhinitis; Respiratory disease; Filaggrin; Asthma; Atopy; Phenotype; Immunology; Bronchus disease; ENT disease; Genetics; Obstructive pulmonary disease; Mutation
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2006.07.026

Childhood eczema often precedes the development of asthma and allergic rhinitis in the so-called atopic march. Recently, 2 loss-of-function mutations in the gene encoding the epidermal barrier protein filaggrin were reported to be predisposing factors for eczema and concomitant asthma, suggesting a possible role in disease transition. We aimed to assess the importance of filaggrin loss-of-function mutations in the susceptibility to eczema and associated clinical phenotypes. The filaggrin mutations were genotyped and tested for association with allergic disorders in 2 large European populations including 1092 children with eczema. Highly significant association of the filaggrin null mutations with eczema and concomitant asthma was replicated. Moreover, we found that these mutations predispose to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema. We show that the presence of 2 filaggrin null alleles is an independent risk factor for asthma in children with eczema, and that the 2 investigated mutations account for about 11% of eczema cases in the German population. These results lend strong support to the role of filaggrin in the pathogenesis of eczema and in the subsequent progression along the atopic march. The fact that previous expression of eczema is a prerequisite for the manifestation of allergic airways disease and specific sensitization highlights the importance of the epidermal barrier in the pathogenesis of these disorders. Our results suggest that the maintenance and repair of the epidermal barrier in infants with eczema may prevent the subsequent development of allergic airways disease.