Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

TY - JOUR

T1 - Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

AU - Palmer, Colin N. A.

AU - Irvine, Alan D.

AU - Terron-Kwiatkowski, Ana

AU - Zhao, Yiwei

AU - Liao, Haihui

AU - Lee, Simon P.

AU - Goudie, David R.

AU - Sandilands, Aileen

AU - Campbell, Linda E.

AU - Smith, Frances J. D.

AU - O'Regan, Grainne M.

AU - Watson, Rosemarie M.

AU - Cecil, Jo E.

AU - Bale, Sherri J.

AU - Compton, John G.

AU - DiGiovanna, John J.

AU - Fleckman, Philip

AU - Lewis-Jones, Sue

AU - Arseculeratne, Gehan

AU - Sergeant, Ann

AU - Munro, Colin S.

AU - El Houate, Brahim

AU - McElreavey, Ken

AU - Halkjaer, Liselotte B.

AU - Bisgaard, Hans

AU - Mukhopadhyay, Somnath

AU - McLean, W. H. Irwin

N1 - dc.publisher: Nature Publishing Group Senior author responsible for overall strategy, funding, planning, analysis and writing of the first paper to show that mutations in the filaggrin gene are the major genetic susceptibility factor in atopic dermatitis and contribute to asthma driven by pre-existing eczema. This award-winning research has changed the landscape of eczema research. dc.description.sponsorship: Wellcome Trust Senior Research Fellowship Dystrophic Epidermolysis Bullosa Research Association Pachyonychia Congenita Project British Skin Foundation/National Eczema Society Biotechnology and Biological Sciences Research Council Award D13460 Scottish Enterprise Tayside and the Gannochy Trust Scottish Executive Genetic Health Initiative

PY - 2006/4

Y1 - 2006/4

N2 - Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects ~20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by ~9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

AB - Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects ~20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by ~9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

U2 - 10.1038/ng1767

DO - 10.1038/ng1767

M3 - Article

SN - 1061-4036

VL - 38

SP - 441

EP - 446

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -