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 decades and now affects approximately 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 approximately 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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Perturbed barrier function is critical for the development of atopic dermatitis and other allergic disorders, namely atopic march.
“Perturbed barrier function is critical for the development of not only atopic dermatitis but also other allergic disorders, namely, atopic march [8,9,10,11].”
From Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway (2017) · cites this paper as [10]
Loss-of-function mutation of the FLG gene is associated with the development of atopic dermatitis.
“loss-of-function mutation of the FLG gene is associated with the development of atopic dermatitis [10,11]”
From Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway (2017) · cites this paper as [10]
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- Authors
- Palmer, C. N. A., Irvine, A. D., Terron-Kwiatkowski, A., Zhao, Y., Liao, H., Lee, S. P., Goudie, D. R., Sandilands, A., Campbell, L. E., Smith, F. J. D., O'Regan, G. M., Watson, R. M., Cecil, J. E., Bale, S. J., Compton, J. G., DiGiovanna, J. J., Fleckman, P., Lewis-Jones, S., Arseculeratne, G., Sergeant, A., Munro, C. S., El Houate, B., McElreavey, K., Halkjaer, L. B., Bisgaard, H., Mukhopadhyay, S., & McLean, W. H. I.
- Affiliations
- University of Dundee (GB)
- Children's Health Ireland at Crumlin (IE)
- Ninewells Hospital (GB)
- National Institutes of Health (US)
- University of Washington (US)
- Institut Pasteur (FR)
- Copenhagen University Hospital (DK)
- Corresponding author
- McLean, W H Irwin
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-03-19
- Volume
- 38
- Issue
- 4
- Pages
- 441-446
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2068176013
- Cited by
- 2,978
- References
- 2
- Citations by year
- 2026: 104 · 2025: 103 · 2024: 149 · 2023: 109 · 2022: 121 · 2021: 129 · 2020: 132 · 2019: 127 · 2018: 143 · 2017: 167 · 2016: 184 · 2015: 156 · 2014: 167 · 2013: 156 · 2012: 175
- FWCI
- 183.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- filaggrin, FLG gene, atopic dermatitis, loss-of-function mutations, 2282del4, skin barrier function, skin barrier, asthma, atopic diseases, genetic susceptibility, heritability, European populations
- MeSH terms
- Filaggrin Proteins, Alleles, Asthma, Child, Dermatitis, Atopic, Female, Humans, Intermediate Filament Proteins, Male, Mutation, Pedigree, Skin Physiological Phenomena, Cohort Studies, Genetic Predisposition to Disease
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