Toward a major risk factor for atopic eczema: Meta-analysis of filaggrin polymorphism data

Institute for Medical Statistics and Epidemiology (IMSE), Technical University Munich (TUM), Munich, Germany.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 01/2008; 120(6):1406-12. DOI: 10.1016/j.jaci.2007.08.067
Source: PubMed


With an impressive series of replication studies, filaggrin (FLG) has become the gene with the most widely replicated association to atopic eczema (AE). However, studies published to date demonstrate differences concerning study design and strength of associations.
We sought to provide a general and overall estimate of FLG effect sizes and to estimate allele and carrier frequencies.
We searched Medline and Institute for Scientific Information Web of Knowledge databases for relevant studies and abstracts from professional societies that were published through June 30, 2007. Initially, we accounted for different study types and evaluated an overall estimate for case-control and family studies. In a second step, we combined those 2 study types and used a random-effects analysis approach to calculate overall odds ratios (ORs). Tests of asymmetry were applied to detect potential publication bias.
Nine studies that met the inclusion criteria were included in the meta-analysis. For the combined genotype (R501X or 2282del4), we found an overall OR of 4.09 (95% CI, 2.64-6.33) from the case-control studies and a summary OR of 2.06 (95% CI, 1.76-2.42) from the family studies.
The powerful effect of FLG variation on AE risk exceeds that of any other investigated candidate gene for AE thus far and makes FLG one of the strongest genes known to date for complex diseases.
These results underline the importance of a genetically determined epidermal barrier disruption in AE.

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Available from: Alan Irvine, Feb 08, 2015
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    • "Filaggrin gene defects may exist in as many as 50% of atopic dermatitis patients [20] [21]. Meta-analysis of filaggrin polymorphism data has identified a genetic alteration in filaggrin as a significant risk for development of atopic dermatitis [22]. The results of filaggrin gene mutations are striking as several studies have demonstrated that the severity of atopic dermatitis correlates with the number of filaggrin gene defects [23] [24] [25] [26] "
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    ABSTRACT: Atopic dermatitis can be due to a variety of causes from nonatopic triggers to food allergy. Control of egress of water and protection from ingress of irritants and allergens are key components of cutaneous barrier function. Current research suggests that a degraded barrier function of the skin allows the immune system inappropriate access to environmental allergens. Epidermal aeroallergen exposure may allow sensitization to allergen possibly initiating the atopic march. Further research into connections between epidermal barrier function and possible allergen sensitization will be important to undertake. Future clinical trials focused on skin barrier protection may be of value as a possible intervention in prevention of the initiation of the atopic march.
    Full-text · Article · May 2012 · Journal of Allergy
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    • "FLG Copy Number Variation and AD Risk complex traits such as atopic dermatitis. Loss-of-function mutations in FLG represent the strongest and most significant genetic factor in the etiology of atopic dermatitis characterized to date (Baurecht et al., 2007; Rodríguez et al., 2009; van den Oord and Sheikh, 2009), with an odds ratio estimated by meta-analysis to be 3.12 (Baurecht et al., 2007). This study contributes to the understanding of haploinsufficiency in atopic dermatitis by showing that CNV within FLG also significantly affects atopic dermatitis risk. "
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    ABSTRACT: Loss-of-function variants within the filaggrin gene (FLG) increase the risk of atopic dermatitis. FLG also demonstrates intragenic copy number variation (CNV), with alleles encoding 10, 11, or 12 filaggrin monomers; hence, CNV may affect the amount of filaggrin expressed in the epidermis. A total of 876 Irish pediatric atopic dermatitis cases were compared with 928 population controls to test the hypothesis that CNV within FLG affects the risk of atopic dermatitis independently of FLG-null mutations. Cases and controls were screened for CNV and common FLG-null mutations. In this population the 11-repeat allele was most prevalent (allele frequency 51.5%); the 10-repeat allele frequency was 33.9% and the 12-repeat allele frequency was 14.6%. Having excluded FLG mutation carriers, the control group had a significantly higher number of repeats than cases (χ(2) P=0.043), and the odds ratio of disease was reduced by a factor of 0.88 (95% confidence interval 0.78-0.98, P=0.025) for each additional unit of copy number. Breakdown products of filaggrin were quantified in tape-stripped stratum corneum from 31 atopic dermatitis patients and urocanic acid showed a positive correlation with total copy number. CNV within FLG makes a significant, dose-dependent contribution to atopic dermatitis risk, and therefore treatments to increase filaggrin expression may have therapeutic utility.
    Full-text · Article · Nov 2011 · Journal of Investigative Dermatology
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    • "In their study 15 families have been studied; AD was present in 44% of individuals heterozygous for this gene and in 76% of homozygous individuals; none of the family member without mutation had AD. Actually it is thought that the frequency of null FLG mutations (5 in total) is 9% in the European population [9]. "
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    ABSTRACT: Objective. In this paper the authors review the management of atopic dermatitis (AD) and the association between AD and allergic respiratory diseases. Data Sources. PubMed databases, researching articles in the last 15 years. Results. Studies about atopic march are cross-sectional population studies at different ages. They show that the most important predisposing factor for atopy is a decrease of the filaggrin's expression. Conclusions. The most modern theories seem to show that the most important factor which starts the atopic march is represented by an impaired epidermal barrier. It causes an increase in skin permeability to allergens that could induce sensitization even in the airways. The major predisposing factor is a primary inherited epithelial barrier defect resulting from filaggrin gene mutation, but other factors may play a role in this complex mechanism. Further studies are needed to focus on AD treatment and preventive strategies.
    Full-text · Article · Sep 2011 · Journal of Allergy
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