Atopic dermatitis and skin disease
Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic disease

https://doi.org/10.1016/j.jaci.2009.03.036Get rights and content

Background

The discovery of filaggrin (FLG) null mutations as a major risk factor for eczema represents a milestone toward the understanding of an important mechanism in this complex disease. However, published studies demonstrate differences concerning design and effect size, and conflicting results for asthma have been reported.

Objectives

We sought to provide a more accurate estimate of FLG effect sizes and to better refine FLG risk profiles within the broad and inclusive eczema diagnosis. We also sought to provide a more detailed and conclusive estimate of the risk for asthma associated with FLG null alleles.

Methods

We performed a meta-analysis of 24 studies on FLG mutations and eczema involving 5,791 cases, 26,454 control subjects, and 1,951 families as well as 17 studies on asthma involving 3,138 cases, 17,164 control subjects, and 1,511 offspring.

Results

Both case-control and family studies showed strong associations with eczema. Case-control studies were heterogeneous, whereas family studies yielded more homogeneous results. Combined analysis showed that FLG haploinsufficiency strongly increases the eczema risk (odds ratio [OR], 3.12; 95% CI, 2.57-3.79) and is associated with more severe and dermatologist-diagnosed disease. FLG mutations are also significantly associated with asthma (OR, 1.48; 95% CI, 1.32-1.66). However, although strong effects for the compound phenotype asthma plus eczema (OR, 3.29; 95% CI, 2.84-3.82) were observed, there appears to be no association with asthma in the absence of eczema.

Conclusions

This meta-analysis summarizes the strong evidence for a high eczema risk conferred by FLG mutations and refines their risk profiles, suggesting an association with more severe and secondary care disease. FLG mutations are also a robust risk factor for asthma and might help define the asthma endophenotype linked with eczema.

Section snippets

Data extraction and abstraction

The extant nosology of atopic disease is confusing, and terms such as eczema, atopic eczema, and atopic dermatitis are frequently used interchangeably in the literature. Recently, a World Allergy Organization report suggested the use of eczema as preferable to atopic dermatitis.8 Following this definition, the term eczema includes the disease formerly called atopic eczema or atopic dermatitis, as well as nonatopic eczema, whereas the term atopic eczema is reserved for those patients with eczema

Results

A total of 89 publications, including published abstracts (35 from PubMed and 54 from the ISI Web of Knowledge) were identified, of which 24 met the inclusion criteria for the current meta-analyses on eczema, asthma, or both. Tables I and II list all case-control and family-based studies included and show the estimated ORs and

Discussion

This meta-analysis of genetic association studies on the most common FLG variants in European populations involved 5,791 eczema cases and 26,454 control subjects, as well as 1,951 families. In addition, 3,138 asthma cases, 17,164 control subjects, and 4 family studies with 1,511 asthma-affected offspring were analyzed. This analysis provides the most comprehensive assessment thus far of the relevance of common FLG polymorphisms to eczema and represents the first meta-analysis on their effect on

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    Supported by grant 01GS0818 of the German Ministry of Education and Research (BMBF) as part of the National Genome Research Network (NGFN). S. Weidinger is supported by a Heisenberg fellowship (WE 2678/4-1) of the DFG, grant C49-08 of the University Hospital Rechts der Isar, Technische Universität München, and a grant from the Wilhelm-Vaillant-Stiftung. S. Weidinger and S. Wagenpfeil are supported by research grants KKF-07/04 and KKF-27/05 of the University Hospital Rechts der Isar, Technische Universität München.

    Disclosure of potential conflict of interest: S. Wagenpfeil has received research support from Bundesministerium für Bildung und Forschung. S. J. Brown has received research support from the British Skin Foundation, the British Society of Paediatric Dermatology, and Action Medical Research. H. J. Cordell has received research support from the Wellcome Trust, the Medical Research Council (UK), and Action Medical Research. A. D. Irvine served as a consultant for Novartis, has received research support from the Children's Medical and Research Foundation and the Health Research Board Ireland, and has provided medicolegal consultations. The rest of the authors have declared that they have no conflict of interest.

    These authors contributed equally to this work.

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