Loss-of-Function Variations Within the Filaggrin Gene Predispose for Atopic Dermatitis With Allergic Sensitizations

Abstract

Weidinger S, Illig T, Baurecht H, et al. J Allergy Clin Immunol. 2006;118:214–219 PURPOSE OF THE STUDY. Evaluation for genetic basis for impaired epidermal skin barrier in atopic dermatitis (AD). STUDY POPULATION. White German families with AD (N = 476). METHODS. Evaluation of the association of the loss-of-function mutations Arg501Xaa and 2282del4 within the filaggrin (FLG) gene by using the transmission-disequilibrium test. RESULTS. This study revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, an association of the FLG mutations was made in particular with the extrinsic subtype of AD, which is characterized by high total serum immunoglobulin E levels and concomitant allergic sensitization. Furthermore, FLG mutations were significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSIONS. These data implicate FLG as the first strong genetic factor identified in a common complex disease. REVIEWER COMMENTS. These findings confirm the importance of FLG as a genetic factor in AD as found by other investigators. This is the strongest genetic evidence to date to identify a cause of the breakdown of the epidermal barrier in AD. Filaggrin may be the “mortar” that is essential within the “bricks” of keratinocytes to maintain the integrity of the epithelial barrier. These findings further support the crucial role of the skin barrier in preventing allergic sensitization.