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

Colin N. A. Palmer, Alan D. Irvine, Ana Terron-Kwiatkowski, Yiwei Zhao, Haihui Liao, Simon P. Lee, David R. Goudie, Aileen Sandilands, Linda E. Campbell, Frances J. D. Smith, Grainne M. O'Regan, Rosemarie M. Watson, Jo E. Cecil, Sherri J. Bale, John G. Compton, John J. DiGiovanna, Philip Fleckman, Sue Lewis-Jones, Gehan Arseculeratne, Ann SergeantColin S. Munro, Brahim El Houate, Ken McElreavey, Liselotte B. Halkjaer, Hans Bisgaard, Somnath Mukhopadhyay, W. H. Irwin McLean

    Research output: Contribution to journalArticlepeer-review

    2044 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)441-446
    Number of pages6
    JournalNature Genetics
    Volume38
    Issue number4
    DOIs
    Publication statusPublished - Apr 2006

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