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

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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Figure 1: Pedigrees of the nine families studied with semidominant inheritance of ichthyosis vulgaris and atopic dermatitis ('eczema').
Figure 2: Filaggrin variants represent a substantial fraction of individuals with asthma and atopic dermatitis (AD).

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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.

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Correspondence to W H Irwin McLean.

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Supplementary information

Supplementary Table 1

Characteristics of atopic dermatitis and asthma subjects with and without FLG variants. (PDF 72 kb)

Supplementary Table 2

Allele frequencies of FLG mutations R501X and 2282del4 in human populations. (PDF 62 kb)

Supplementary Table 3

PCR primers and probes used for genotyping of FLG variants. (PDF 45 kb)

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Palmer, C., Irvine, A., Terron-Kwiatkowski, A. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38, 441–446 (2006). https://doi.org/10.1038/ng1767

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