Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march.
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.
Marenholz
Ingo
I
Pediatric Pneumology and Immunology, Charité University Medicine, Berlin, Germany.
Nickel
Renate
R
Rüschendorf
Franz
F
Schulz
Florian
F
Esparza-Gordillo
Jorge
J
Kerscher
Tamara
T
Grüber
Christoph
C
Lau
Susanne
S
Worm
Margitta
M
Keil
Thomas
T
Kurek
Michael
M
Zaluga
Elisabetha
E
Wahn
Ulrich
U
Lee
Young-Ae
YA
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
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins