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

Article · January 2008with73 Reads
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.
    • The reason for this is still being discussed but shared genetic factors are a possible cause[6]. Since the identification of loss-of-function variants at the filaggrin (FLG) locus as strong and widely replicated risk factors for AD[7]there is increasing evidence for the central role of epidermal barrier defects in predisposing to AD[8][9][10]. Interestingly, the FLG defects have also been associated with an increased risk for development of other allergic diseases such as allergic rhinitis (AR) and atopic asthma (AA) also in the absence of AD[10]. In particular, in a recent study in a Polish population we have found that two most frequent FLG null variants 2282del4 and R501X were associated not only with AD but also with AA and persistent allergic rhinitis (pAR)[11].
    [Show abstract] [Hide abstract] ABSTRACT: The T allele of rs7927894 (at 11q13.5) was associated with atopic dermatitis and other allergic diseases. Our purpose was to replicate the association with allergic phenotypes and explore the role of rs7927894 in predisposing to persistent allergic rhinitis and atopic asthma. We also wanted to explore if other SNPs at 11q13.5 contributed to effect of rs7927894. We studied patients with atopic dermatitis (N = 270), atopic asthma (N = 486), persistent allergic rhinitis (N = 589) and controls matched for age, sex and region (N = 540, N = 372 and N = 1178, respectively). We found that rs7927894 T was associated with atopic dermatitis (OR = 1.39, CI: 1.12–1.73, P = 0.003) and independently with persistent allergic rhinitis (OR = 1.24, CI:1.07–1.43, P = 0.0043, Pcorrected = 0.013) but not atopic asthma. Analysis of additional tagging SNPs (rs7930763, rs2513517, rs7125552) showed that effect of rs7927894 T was limited to haplotypes encoding G at rs7125552. In conclusion, rs7927894 T is associated not only with atopic dermatitis but also persistent allergic rhinitis. Since these effects are haplotype dependent rs7927894 alone does not account for the association between 11q13.5 and atopic dermatitis/persistent allergic rhinitis.
    Full-text · Article · Sep 2017
    • Skin barrier defects caused by FLG mutations allows the penetration of allergens through the epidermis and their interaction with antigen-presenting cells, leading to the development of atopic disorders, including asthma and rhinitis [11]. Recent studies demonstrated that FLG mutations are strongly associated with increased atopic eczema risk, and probably account for approximately 10% of cases in Europe [12]. AD may persist with a chronic recurrent course until adulthood and this subtype is often very recalcitrant to any treatment strategy1314.
    [Show abstract] [Hide abstract] ABSTRACT: Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease which predominantly affects children usually clearing up during or after childhood. However, AD may persist with a chronic recurrent course until adulthood being recalcitrant to any treatment strategy. Moreover, in some patients, AD is not present during childhood but starts later in life (i.e. after 16 years of age) being defined late--onset AD. Even if AD incidence is increasing worldwide with cases in which clinical manifestations first appeared or persisted during adolescence and adulthood raising especially in industrialized countries, studies on adult AD are still scant. Since this subgroup of AD patients often have a nonflexural rash distribution and atypical morphologic variants and validated diagnostic criteria are lacking, there is no clear consensus on the diagnostic work--up that should be performed when evaluating adult patients with AD. In this review, the various aspects of workup in adult patients with AD, such as diagnostic criteria, epidemiology, quality of life and pathogenesis are discussed.
    Full-text · Article · Feb 2015
    • Yet one of the hallmarks of atopic dermatitis is the presence of generally dry skin even in the absence of inflammation[26], an observation that stimulated researchers in Dundee to look at the genes that may be responsible for other dry skin conditions such as ichthyosis[10]. They found that mutations of genes that code for filaggrin – a key protein in the outer skin that maintains skin barrier function – are a strong predictor of atopic dermatitis, especially more severe, chronic atopic dermatitis and associated asthma[27,28]. So the world of atopic dermatitis research is turning its attention away from the inside of the body to the dry skin on the outside.
    [Show abstract] [Hide abstract] ABSTRACT: Atopic dermatitis now affects one in five children, and may progress to asthma and hay fever. In the absence of effective treatments that influence disease progression, prevention is a highly desirable goal. The evidence for most existing disease prevention strategies, such as avoidance of allergens and dietary interventions, has been unconvincing and inconsistent. Fresh approaches to prevention include trying to induce tolerance to allergens in early life, and enhancing the defective skin barrier to reduce skin inflammation, sensitisation and subsequent allergic disease. Early and aggressive treatment of atopic dermatitis represents another possible secondary prevention strategy that could interrupt the development of autoimmunity, which may account for atopic dermatitis persistence. Large scale and long term randomized controlled trials are needed to demonstrate that these ideas result in clinical benefit.
    Full-text · Article · Dec 2012
    • The recent discovery of filaggrin gene (FLG) polymorphisms in the pathogenesis of AD was a significant breakthrough in our understanding of AD56789101112. FLG mutations have thus far been found in up to 20 % of AD patients and may be associated with greater severity [9, 13]. SPINK5, a serine protease inhibitor involved in the regulation of stratum corneum thickness and function, is another gene of interest in AD.
    [Show abstract] [Hide abstract] ABSTRACT: Atopic dermatitis (AD) is a significant cause of morbidity and healthcare costs in the United States and worldwide. The prevalence of AD in childhood is rising in the United States and other developed countries for reasons that are not well understood. Similarly, the prevalences of obesity and diabetes are on the rise, which might be contributing toward increased AD. This article reviews the association between AD and other atopic disorders with obesity and diabetes. Furthermore, recently recognized AD comorbidities, including fatty liver disease and erectile dysfunction, are reviewed. Potential mechanisms for the association between AD and metabolic disorders are discussed.
    Full-text · Article · Dec 2012
    • Based on the existing data, in AE and asthma, locally acting target-organ-specific genes which affect epithelial barrier function as well as ''atopy'' and ''inflammation'' genes which determine immune response patterns appear to be important (Brown, 2009; Vercelli, 2008). For AE, variants in the FLG gene, which encodes a key epidermal structural protein, are the strongest known risk factor (Baurecht et al., 2007; Rodriguez et al., 2009). Furthermore, several candidate genes with, however, rather small effects encoding major elements of the immune system such as innate immune receptors and proteins involved in the regulation of TH1/TH2 differentiation and effector function have been reported for various atopic traits (Holloway and Holgate, 2010 ).
    [Show abstract] [Hide abstract] ABSTRACT: Epidemiological data indicate that atopic eczema (AE) in infancy significantly increases the risk for attention deficit/hyperactivity disorder (ADHD) in later life. The underlying pathophysiological mechanisms of this comorbidity are unknown. We propose that the release of inflammatory cytokines caused by the allergic inflammation and/or elevated levels of psychological stress as a result of the chronic disease interfere with the maturation of prefrontal cortex regions and neurotransmitter systems involved ADHD pathology. Alternatively, increased stress levels in ADHD patients may trigger AE via neuroimmunological mechanisms. In a third model, AE and ADHD may be viewed as two separate disorders with one or more shared risk factors (e.g., genetics, prenatal stress) that increase the susceptibility for both disorders leading to the co-occurrence of AE and ADHD. Future investigation of these three models may lead to a better understanding of the mechanisms underlying the observed comorbidity between AE and ADHD and further, to targeted interdisciplinary primary prevention and treatment strategies.
    Article · Nov 2012
    • 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]
    [Show abstract] [Hide abstract] 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
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