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

Nature Genetics 38, 441–446 (2006) | Download Citation

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Abstract

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades1 and now affects ∼20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable2. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated3. 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.

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Acknowledgements

We thank the patients and their families for their participation which made this research possible, K. Johnston for clinical assistance, and the following at Ninewells Hospital and Medical School: J. Hands, N. Joy and C. Black, Molecular Genetics Laboratory, for DNA extraction and storage; A. Cassidy, G. Scott and G. McGregor, DNA Analysis Facility, for genotyping support; I. Murrie, T. Ismail, Children's Asthma and Allergy Unit, for field work and data entry and J. Mcfarlane, Epithelial Genetics Group for clerical assistance. We thank M. Greenway, National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland for providing Irish control samples. We thank H. Williams, University of Nottingham, UK for permission to use the Nottingham Eczema Severity Score. This work was supported by a Wellcome Trust Senior Research Fellowship (W.H.I.M.), the Odland Endowed Research Fund (P.F.), as well as grants from the Dystrophic Epidermolysis Bullosa Research Association (W.H.I.M.), the Pachyonychia Congenita Project (F.J.D.S.), the British Skin Foundation/National Eczema Society (F.J.D.S. & W.H.I.M.), the Biotechnology and Biological Sciences Research Council (award D13460; C.N.A.P.), Scottish Enterprise Tayside and the Gannochy Trust (C.N.A.P. and S.M.). C.N.A.P. is also supported by the Scottish Executive Genetic Health Initiative. K. McE. is supported by GIS, Institut des maladies rares. G.M.O'R. is supported by a grant from the Children's Medical and Research Foundation, Our Lady's Hospital for Sick Children, Dublin.

Author information

    • Colin N A Palmer
    •  & Alan D Irvine

    These authors contributed equally to this work.

Affiliations

  1. Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

    • Colin N A Palmer
    •  & Simon P Lee

  2. Department of Paediatric Dermatology, Our Lady's Hospital for Sick Children, Crumlin, Dublin 12, Ireland.

    • Alan D Irvine
    • , Gráinne M O'Regan
    •  & Rosemarie M Watson

  3. Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

    • Ana Terron-Kwiatkowski
    • , Yiwei Zhao
    • , Haihui Liao
    • , Aileen Sandilands
    • , Linda E Campbell
    • , Frances J D Smith
    •  & W H Irwin McLean

  4. Clinical Genetics, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

    • David R Goudie

  5. The Bute Medical School, University of St. Andrews, St. Andrews, Fife, Scotland, UK.

    • Jo E Cecil

  6. GeneDx, Gaithersburg, Maryland 20877, USA.

    • Sherri J Bale
    •  & John G Compton

  7. Division of Dermatopharmacology, Department of Dermatology, Brown Medical School and Rhode Island Hospital, Providence, Rhode Island 02903, USA.

    • John J DiGiovanna

  8. Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • John J DiGiovanna

  9. Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.

    • Philip Fleckman

  10. Dermatology, Tayside University Hospitals NHS Trust, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.

    • Sue Lewis-Jones
    •  & Gehan Arseculeratne

  11. Department of Dermatology, South Glasgow University Hospitals NHS Trust, Glasgow G51 4TF, UK.

    • Ann Sergeant
    •  & Colin S Munro

  12. Reproduction, Fertility and Populations, Institut Pasteur, 75724 Paris, France.

    • Brahim El Houate
    •  & Ken McElreavey

  13. Danish Paediatric Asthma Centre, Copenhagen, University Hospital, DK-2900 Gentofte, Copenhagen, Denmark.

    • Liselotte B Halkjaer
    • , Hans Bisgaard
    •  & Somnath Mukhopadhyay

  14. Children's Asthma and Allergy Research Unit, Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to W H Irwin McLean.

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    Characteristics of atopic dermatitis and asthma subjects with and without FLG variants.

  2. 2.

    Supplementary Table 2

    Allele frequencies of FLG mutations R501X and 2282del4 in human populations.

  3. 3.

    Supplementary Table 3

    PCR primers and probes used for genotyping of FLG variants.

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DOI

https://doi.org/10.1038/ng1767

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