Letter abstract
Nature Genetics 39, 650 - 654 (2007)
Published online: 8 April 2007 | doi:10.1038/ng2020
Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema
Aileen Sandilands1, Ana Terron-Kwiatkowski1, Peter R Hull1, Gráinne M O'Regan2, Timothy H Clayton2, Rosemarie M Watson2, Thomas Carrick3, Alan T Evans4, Haihui Liao1, Yiwei Zhao1, Linda E Campbell1, Matthias Schmuth5, Robert Gruber5, Andreas R Janecke6, Peter M Elias7, Maurice A M van Steensel8, Ivo Nagtzaam8, Michel van Geel8, Peter M Steijlen8, Colin S Munro9, Daniel G Bradley10, Colin N A Palmer11, Frances J D Smith1, W H Irwin McLean1,13 & Alan D Irvine2,12,13
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris1 and predispose to eczema and secondary allergic diseases2. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (
2 test: P = 2.12 
10-51; Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9–11.3), and homozygote OR = 151 (95% c.i. = 20–1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.
- Epithelial Genetics Group, Human Genetics Unit, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
- Department of Paediatric Dermatology, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
- Department of Genetics Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
- Department of Pathology, Tayside University Hospitals NHS Trust, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
- Department of Dermatology Innsbruck Medical University, Innsbruck, Austria.
- Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria.
- Dermatology and Metabolism (Medicine) Services, Veterans Affairs Medical Center, San Francisco, California, USA.
- Department of Dermatology, University Hospital Maastricht, Maastricht, The Netherlands.
- Department of Dermatology, Southern General Hospital, Glasgow, UK.
- Department of Genetics, Trinity College Dublin, Dublin 2, Ireland.
- Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
- Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
- These authors contributed equally to this work.
Correspondence to: W H Irwin McLean1,13 e-mail: w.h.i.mclean@dundee.ac.uk
Correspondence to: Alan D Irvine2,12,13 e-mail: irvinea@tcd.ie
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