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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References
Holgate, S.T. The epidemic of allergy and asthma. Nature 402, B2–B4 (1999).
Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430 (2002).
Cookson, W.O. & Moffatt, M.F. The genetics of atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 2, 383–387 (2002).
Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 6, 328–340 (2005).
Listwan, P. & Rothnagel, J.A. Keratin bundling proteins. Methods Cell Biol. 78, 817–827 (2004).
Gan, S.Q., McBride, O.W., Idler, W.W., Markova, N. & Steinert, P.M. Organization, structure, and polymorphisms of the human profilaggrin gene. Biochemistry 29, 9432–9440 (1990).
Presland, R.B. & Dale, B.A. Epithelial structural proteins of the skin and oral cavity: function in health and disease. Crit. Rev. Oral Biol. Med. 11, 383–408 (2000).
Compton, J.G., DiGiovanna, J.J., Johnston, K.A., Fleckman, P. & Bale, S.J. Mapping of the associated phenotype of an absent granular layer in ichthyosis vulgaris to the epidermal differentiation complex on chromosome 1. Exp. Dermatol. 11, 518–526 (2002).
Smith, F.J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38, 337–342 (2006).
Bisgaard, H. The Copenhagen prospective study on asthma in childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. Ann. Allergy Asthma Immunol. 93, 381–389 (2004).
Masoli, M., Fabian, D., Holt, S. & Beasley, R. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59, 469–478 (2004).
Spergel, J.M. & Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 112, S118–S127 (2003).
Tabata, N., Tagami, H. & Kligman, A.M. A twenty-four-hour occlusive exposure to 1% sodium lauryl sulfate induces a unique histopathologic inflammatory response in the xerotic skin of atopic dermatitis patients. Acta Derm. Venereol. 78, 244–247 (1998).
Seguchi, T. et al. Decreased expression of filaggrin in atopic skin. Arch. Dermatol. Res. 288, 442–446 (1996).
Jensen, J.M. et al. Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J. Invest. Dermatol. 122, 1423–1431 (2004).
Sugiura, H. et al. Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br. J. Dermatol. 152, 146–149 (2005).
Cookson, W.O. et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat. Genet. 27, 372–373 (2001).
Wells, R.S. & Kerr, C.S. Clinical features of autosomal dominant and sex-linked ichthyosis in an English Population. Br. Med. J. 1, 947–950 (1966).
Kuokkanen, K. Ichthyosis vulgaris. A clinical and histopathological study of patients and their close relatives in the autosomal dominant and sex-linked forms of the disease. Acta Derm. Venereol. Suppl. (Stockh.) 62, 1–72 (1969).
Tay, Y.K., Khoo, B.P. & Goh, C.L. The epidemiology of atopic dermatitis at a tertiary referral skin center in Singapore. Asian Pac. J. Allergy Immunol. 17, 137–141 (1999).
Wang, L.F., Lin, J.Y., Hsieh, K.H. & Lin, R.H. Epicutaneous exposure of protein antigen induces a predominant Th2-like response with high IgE production in mice. J. Immunol. 156, 4077–4082 (1996).
Spergel, J.M. et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J. Clin. Invest. 101, 1614–1622 (1998).
Ginger, R.S., Blachford, S., Rowland, J., Rowson, M. & Harding, C.R. Filaggrin repeat number polymorphism is associated with a dry skin phenotype. Arch. Dermatol. Res. 297, 235–241 (2005).
Kurz, T. et al. A genome-wide screen on the genetics of atopy in a multiethnic European population reveals a major atopy locus on chromosome 3q21.3. Allergy 60, 192–199 (2005).
Wuthrich, B. & Schmid-Grendelmeier, P. The atopic eczema/dermatitis syndrome. Epidemiology, natural course, and immunology of the IgE-associated (“extrinsic”) and the nonallergic (“intrinsic”) AEDS. J. Investig. Allergol. Clin. Immunol. 13, 1–5 (2003).
Williams, H.C., Burney, P.G., Pembroke, A.C. & Hay, R.J. The U.K. Working Party's diagnostic criteria for atopic dermatitis. III. Independent hospital validation. Br. J. Dermatol. 131, 406–416 (1994).
Williams, H.C. et al. The U.K. Working Party's diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br. J. Dermatol. 131, 383–396 (1994).
Emerson, R.M., Charman, C.R. & Williams, H.C. The Nottingham eczema severity score: preliminary refinement of the Rajka and Langeland grading. Br. J. Dermatol. 142, 288–297 (2000).
Cecil, J.E. et al. The Pro12Ala and C-681G variants of the PPARG locus are associated with opposing growth phenotypes in young schoolchildren. Diabetologia 48, 1496–1502 (2005).
Brydensholt, H.L. et al. Development of atopic dermatitis during the first 3 years of life. The COPSAC cohort study in high-risk children. Arch. Dermatol. (in the press).
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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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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DOI: https://doi.org/10.1038/ng1767
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