Filaggrin Loss-of-Function Mutations Predispose to Phenotypes Involved in the Atopic March

Abstract

Marenholz I, Nickel R, Rüschendorf F, et al. J Allergy Clin Immunol. 2006;118:866–871 PURPOSE OF THE STUDY. To assess the importance of filaggrin loss-of-function mutations in the susceptibility to eczema and associated clinical phenotypes. STUDY POPULATION. Two large European populations including 1092 children with eczema. METHODS. The filaggrin mutations were genotyped and tested for association with allergic disorders. RESULTS. A highly significant association of the filaggrin null mutations with eczema and concomitant asthma was found. These mutations predisposed to asthma, allergic rhinitis, and allergic sensitization only in the presence of eczema. The presence of 2 filaggrin null alleles was an independent risk factor for asthma in children with eczema, and the 2 investigated mutations accounted for ∼11% of eczema cases in the German population. CONCLUSIONS. These results support 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 in a large subset of patients highlights the importance of the epidermal barrier in the pathogenesis of these disorders. REVIEWER COMMENTS. The filaggrin gene encodes a structural protein that is essential for skin-barrier formation. Infants and children with atopic dermatitis are at high risk for developing additional atopic disorders, including food allergy, allergic rhinitis, and asthma. A disrupted skin barrier may be an important portal of entry for environmental and food allergens. In animal models, exposure through the skin predisposes to development of immunoglobulin E sensitization. Early intensive efforts to maintain and restore skin-barrier function may prevent subsequent development of allergic diseases and stop the progression of the atopic march.