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An update on the genetics of atopic dermatitis: scratching the surface in 2009.

ABSTRACT: A genetic basis for atopic dermatitis (AD) has long been recognized. Historic documents allude to family history of disease as a risk factor. Before characterization of the human genome, heritability studies combined with family-based linkage studies supported the definition of AD as a complex trait in that interactions between genes and environmental factors and the interplay between multiple genes contribute to disease manifestation. A summary of more than 100 published reports on genetic association studies through mid-2009 implicates 81 genes, in 46 of which at least 1 positive association with AD has been demonstrated. Of these, the gene encoding filaggrin (FLG) has been most consistently replicated. Most candidate gene studies to date have focused on adaptive and innate immune response genes, but there is increasing interest in skin barrier dysfunction genes. This review examines the methods that have been used to identify susceptibility genes for AD and how the underlying pathology of this disease has been used to select candidate genes. Current challenges and the potential effect of new technologies are discussed.

SUBMITTER: Barnes KC

PROVIDER: S-EPMC2874322 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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An update on the genetics of atopic dermatitis: scratching the surface in 2009.

Barnes Kathleen C KC

The Journal of allergy and clinical immunology 20100101 1

A genetic basis for atopic dermatitis (AD) has long been recognized. Historic documents allude to family history of disease as a risk factor. Before characterization of the human genome, heritability studies combined with family-based linkage studies supported the definition of AD as a complex trait in that interactions between genes and environmental factors and the interplay between multiple genes contribute to disease manifestation. A summary of more than 100 published reports on genetic asso ...[more]

PMID: 20109730

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Project description:BackgroundChronic scratching imposes a major stress on the skin and can lead to itch intensity worsening, and consequently, patients may enter an itch-scratch cycle. This repetitive mechanical stress can result in lichenification, worsening of epidermal barrier function, and enhanced cutaneous inflammation. Furthermore, a reduction of intraepidermal nerve fibers was previously described in lichenification.AimThe aim of this study was to investigate the influence of chronic scratching on the epidermal neuroanatomy and on sensory changes, in particular the prevalence of hyperknesis and alloknesis in patients after mechanical, chemical, and electrical stimuli.MethodsAnalyses were performed on pruritic lichenified (chronically scratched), pruritic non-lichenified (not chronically scratched), and non-pruritic non-lesional (unaffected) skin areas of patients with inflammatory pruritus, i.e., atopic dermatitis (n = 35), and neuropathic pruritus, i.e., brachioradial pruritus (n = 34) vs. healthy matched controls (n = 64). Our fine-grained spatial skin characterization enabled specifically studying the differential effects of chronic scratching in inflammatory and neuropathic itch.ResultsAnalysis of intraepidermal nerve fiber density showed rarefaction of fibers in all three skin areas of patients compared with healthy controls in both diagnoses. Even more, the two pruritic areas had significantly less nerve fibers than the unaffected skin, whereas electrically induced itch was massively increased. Epidermal branching of the remaining nerve fibers in lichenified/chronically scratched skin was increased, particularly in patients with brachioradial pruritus, which may contribute to the pronounced local neuronal sensitivity. Hyperknesis and alloknesis were found to increase independently of lichenification.ConclusionOur results indicate that chronic scratching may not affect intraepidermal nerve fiber density but leads to a stronger branching pattern of intraepidermal nerve fibers, which may contribute to local hypersensitivity. The increased sensitivity in the pruritic areas suggests mechanisms of peripheral sensitization, whereas the increased sensation of electrically and chemically induced itch in unaffected skin indicates central sensitization for itch.

Project description:BackgroundAtopic dermatitis (AD) is a heterogeneous disease with a multifactorial aetiology and complex pathophysiology. This heterogeneity translates into different trajectories of disease progression with respect to severity, persistence and risk of development of atopic comorbidities. Determining which possible disease trajectories or comorbidities any individual child might develop is challenging in clinical practice. Tools that help identify paediatric patients at higher risk of disease progression would greatly aid clinicians.MethodsWe reviewed recent cohort studies to synthesize and simplify the epidemiological data to try to identify shared clinically relevant characteristics that may help physicians estimate the risk of disease progression in paediatric patients with AD.ResultsDespite the variability in data collection and methods of analysis and their limitations, there are common patterns of early-childhood AD that may aid in the estimation of risk for disease progression. Factors associated with risk of AD progression include younger age of onset, family history of atopy, greater AD severity, filaggrin mutations, urban environment and polysensitization and/or allergic multimorbidity. Based on these factors, we provide a practitioner's guide for identifying, counselling and/or referring infants and children with AD at potentially higher risk of developing persistent AD and atopic comorbidities. We also present clinical scenarios to illustrate how these data relate to real-life situations.ConclusionsUseful insights are provided for physicians and patients to inform them better about the risk of AD progression and to help guide care pathways for the paediatric population with AD. What's already known about this topic? The complex pathophysiology of atopic dermatitis (AD) translates into a heterogeneous clinical presentation and trajectories of disease progression. Although the consensus is that most paediatric patients with AD will eventually 'outgrow' the disease or follow the longitudinal trajectory known as the 'atopic march', a significant proportion will develop persistent AD and/or other atopic conditions. No known factors conclusively predict the risk of progression or development of comorbidities. What does this study add? Recent analyses of data from large cohorts of paediatric patients with AD have suggested the existence of potentially discrete clusters of patients who present with relatively common AD phenotypes. These studies have shed some light onto the factors associated with risk of progression, which we review in this article. A practitioner's guide with clinical scenarios is provided to help identify patients at high risk of progression to determine whether a patient should be monitored and/or would require specialist referral.

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An update on the genetics of atopic dermatitis: scratching the surface in 2009.

Publications

An update on the genetics of atopic dermatitis: scratching the surface in 2009.

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