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

Colin N A Palmer^1, 15, Alan D Irvine^2, 15, Ana Terron-Kwiatkowski³, Yiwei Zhao³, Haihui Liao³, Simon P Lee¹, David R Goudie⁴, Aileen Sandilands³, Linda E Campbell³, Frances J D Smith³, Gráinne M O'Regan², Rosemarie M Watson², Jo E Cecil⁵, Sherri J Bale⁶, John G Compton⁶, John J DiGiovanna^7, 8, Philip Fleckman⁹, Sue Lewis-Jones¹⁰, Gehan Arseculeratne¹⁰, Ann Sergeant¹¹, Colin S Munro¹¹, Brahim El Houate¹², Ken McElreavey¹², Liselotte B Halkjaer¹³, Hans Bisgaard¹³, Somnath Mukhopadhyay¹³ & W H Irwin McLean³

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

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

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

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

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

⁶  GeneDx, Gaithersburg, Maryland 20877, USA.

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

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

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

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

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

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

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

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.

¹⁵  These authors contributed equally to this work.

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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