Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations.
BACKGROUND
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation.


OBJECTIVE
Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD.


METHODS
We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test.


RESULTS
Our family-based approach 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, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris.


CONCLUSIONS
Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease.


CONCLUSIONS
These findings underline the crucial role of the skin barrier in preventing allergic sensitization.
Weidinger
Stephan
S
Department of Dermatology and Allergy Biederstein, Technical University Munich, Biedersteiner Strasse 29, 80802 Munich, Germany. weidinger@lrz.tum.de
Illig
Thomas
T
Baurecht
Hansjörg
H
Irvine
Alan D
AD
Rodriguez
Elke
E
Diaz-Lacava
Amalia
A
Klopp
Norman
N
Wagenpfeil
Stefan
S
Zhao
Yiwei
Y
Liao
Haihui
H
Lee
Simon P
SP
Palmer
Colin N A
CN
Jenneck
Claudia
C
Maintz
Laura
L
Hagemann
Tobias
T
Behrendt
Heidrun
H
Ring
Johannes
J
Nothen
Markus M
MM
McLean
W H Irwin
WH
Novak
Natalija
N
D016022:Case-Control Studies; D003876:Dermatitis, Atopic / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007381:Intermediate Filament Proteins / Q000235:genetics*; D009154:Mutation; D012867:Skin / Q000378:metabolism
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D007073:Immunoglobulin E