title: Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We aimed to assess the importance of filaggrin loss-of-function mutations in the susceptibility to eczema and associated clinical phenotypes.
  
  
  METHODS
  The filaggrin mutations were genotyped and tested for association with allergic disorders in 2 large European populations including 1092 children with eczema.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Marenholz
authors.forename: Renate
authors.initials: R
authors.lastname: Nickel
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Florian
authors.initials: F
authors.lastname: Schulz
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.forename: Tamara
authors.initials: T
authors.lastname: Kerscher
authors.forename: Christoph
authors.initials: C
authors.lastname: Grüber
authors.forename: Susanne
authors.initials: S
authors.lastname: Lau
authors.forename: Margitta
authors.initials: M
authors.lastname: Worm
authors.forename: Thomas
authors.initials: T
authors.lastname: Keil
authors.forename: Michael
authors.initials: M
authors.lastname: Kurek
authors.forename: Elisabetha
authors.initials: E
authors.lastname: Zaluga
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wahn
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
mesh_terms: D001249:Asthma / Q000150:complications / Q000235:genetics*; D002648:Child; D004485:Eczema / Q000150:complications / Q000235:genetics*; D005190:Family; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000150:complications / Q000235:genetics*; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins