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The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study

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Background

Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma.

Objective

We sought to determine the natural history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study.

Methods

We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991.

Results

FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10−8). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10−11). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10−27).

Conclusion

FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the “eczema plus early wheeze” and “eczema plus asthma” phenotypes.

Section snippets

Participants

The ALSPAC is a longitudinal, population-based birth cohort study that recruited 14,541 pregnant women residing in Avon, United Kingdom, with expected dates of delivery between April 1, 1991, and December 31, 1992. There were 14,062 liveborn children. The study protocol has been described previously,6, 7 and further details are available on the ALSPAC Web site (http://www.alspac.bris.ac.uk). Ethical approval for all aspects of data collection was obtained from the ALSPAC Law and Ethics

Results

Each of these 2 mutations is known to have essentially identical biochemical consequences,1, 5 and in this study association scores and penetrance results for the primary phenotypes discussed are very similar for these 2 mutations (see Table E1, Table E2 in the Online Repository at www.jacionline.org); we present and analyze here the combined genotypic data. A summary of genotyping results along with a phenotypic profile of the cohort is given in Table I.

Discussion

Filaggrin is a highly abundant protein in the outermost layers of the epidermis, where it performs a critical cell-compaction process during the formation of the stratum corneum, the terminally differentiated cell layers responsible for skin barrier function.14 Decreased or absent FLG expression because of inheritance of loss-of-function mutations, which are surprisingly prevalent in white populations of European origin, leads to impaired barrier function, allowing the entry of antigens,

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The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children. Measurements of pulmonary function and bronchial responsiveness were supported by a grant from the UK Medical Research Council. This research was specifically funded by the Department of Paediatric Dermatology, Our Lady's Children's Hospital Crumlin, Dublin, and the genotyping was supported by a grant from Tenovus (Tayside) to C.P. and S.M. C.P. is supported by the Chief Scientists Office of the Scottish Executive Generation Scotland Initiative. The McLean laboratory is supported by grants from the British Skin Foundation/National Eczema Association, the Pachyonychia Congenita Project, the Dystrophic Epidermolysis Bullosa Research Association, the Medical Research Council (reference no. G0700314), and anonymous donations from atopic families in the Tayside region of Scotland.

Disclosure of potential conflict of interest: S. P. Lee has received research support from Tenovus Scotland. M. Pembrey has received research support from the Wellcome Trust. C. N. A. Palmer has received research support from Wyeth Pharmaceuticals, Scottish Executive, and the Wellcome Trust. W. H. I. McLean has filed patents on filaggrin. A. D. Irvine has received research support from the Children's Medical and Research Foundation and has served as an expert witness in occupational skin disease litigation. The rest of the authors have reported no conflict of interest.

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