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

References

1. Holgate, S.T. The epidemic of allergy and asthma. Nature 402, B2–B4 (1999).
   Article CAS Google Scholar
2. Van Eerdewegh, P. et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426–430 (2002).
   Article CAS Google Scholar
3. Cookson, W.O. & Moffatt, M.F. The genetics of atopic dermatitis. Curr. Opin. Allergy Clin. Immunol. 2, 383–387 (2002).
   Article Google Scholar
4. 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).
   Article CAS Google Scholar
5. Listwan, P. & Rothnagel, J.A. Keratin bundling proteins. Methods Cell Biol. 78, 817–827 (2004).
   Article CAS Google Scholar
6. 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).
   Article CAS Google Scholar
7. 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).
   Article CAS Google Scholar
8. 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).
   Article CAS Google Scholar
9. Smith, F.J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38, 337–342 (2006).
   Article CAS Google Scholar
10. 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).
    Article Google Scholar
11. 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).
    Article Google Scholar
12. Spergel, J.M. & Paller, A.S. Atopic dermatitis and the atopic march. J. Allergy Clin. Immunol. 112, S118–S127 (2003).
    Article Google Scholar
13. 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).
    Article CAS Google Scholar
14. Seguchi, T. et al. Decreased expression of filaggrin in atopic skin. Arch. Dermatol. Res. 288, 442–446 (1996).
    Article CAS Google Scholar
15. Jensen, J.M. et al. Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. J. Invest. Dermatol. 122, 1423–1431 (2004).
    Article CAS Google Scholar
16. 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).
    Article CAS Google Scholar
17. Cookson, W.O. et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat. Genet. 27, 372–373 (2001).
    Article CAS Google Scholar
18. 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).
    Article CAS Google Scholar
19. 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).
    CAS Google Scholar
20. 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).
    CAS PubMed Google Scholar
21. 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).
    CAS PubMed Google Scholar
22. 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).
    Article CAS Google Scholar
23. 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).
    Article CAS Google Scholar
24. 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).
    Article CAS Google Scholar
25. 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).
    CAS PubMed Google Scholar
26. 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).
    Article CAS Google Scholar
27. 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).
    Article CAS Google Scholar
28. 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).
    Article CAS Google Scholar
29. 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).
    Article CAS Google Scholar
30. 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).

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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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Author notes

1. Colin N A Palmer and Alan D Irvine: These authors contributed equally to this work.

Authors and 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. Division of Pathology and Neuroscience, Epithelial Genetics Group, Human Genetics Unit, 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, 20877, Maryland, USA
   Sherri J Bale & John G Compton
7. Division of Dermatopharmacology, Department of Dermatology, Brown Medical School and Rhode Island Hospital, Providence, 02903, Rhode Island, USA
   John J DiGiovanna
8. Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA
   John J DiGiovanna
9. Division of Dermatology, Department of Medicine, University of Washington, Seattle, 98195, Washington, 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, Paris, 75724, 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
    Somnath Mukhopadhyay

Authors

1. Colin N A Palmer
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2. Alan D Irvine
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3. Ana Terron-Kwiatkowski
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4. Yiwei Zhao
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5. Haihui Liao
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6. Simon P Lee
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7. David R Goudie
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8. Aileen Sandilands
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9. Linda E Campbell
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10. Frances J D Smith
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11. Gráinne M O'Regan
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12. Rosemarie M Watson
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13. Jo E Cecil
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14. Sherri J Bale
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15. John G Compton
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16. John J DiGiovanna
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17. Philip Fleckman
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18. Sue Lewis-Jones
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19. Gehan Arseculeratne
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20. Ann Sergeant
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21. Colin S Munro
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22. Brahim El Houate
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23. Ken McElreavey
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24. Liselotte B Halkjaer
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25. Hans Bisgaard
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26. Somnath Mukhopadhyay
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27. W H Irwin McLean
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Corresponding author

Correspondence toW H Irwin McLean.

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The authors declare no competing financial interests.

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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• Received: 23 December 2005
• Accepted: 24 February 2006
• Published: 19 March 2006
• Issue Date: 01 April 2006
• DOI: https://doi.org/10.1038/ng1767