Die Genetik atopischer Erkrankungen

Allergic disorders (atopic dermatitis, asthma, hay fever) are common chronic inflammatory diseases of the skin and airways that are often associated with allergies (formation of specific IgE antibodies) to environmental allergens. They are complex genetic diseases, so that both genetic and environmental factors are involved in their causation. Most of the research effort devoted to the search for genes that might be responsible has so far focused on the mechanisms behind the immune response. More recent work on gene identification, however, documents the decisive importance of epithelial barrier defects in the pathogenesis of AD and allergic airways disease. These findings represent an important milestone in unraveling the genetic mechanisms underlying these complex diseases and allow new insight into the molecular mechanisms that lead illnesses to develop. In addition, they might point the way to novel preventive and therapeutic strategies for atopic disorders.     

Asthma: a major pediatric health issue

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.     

Interactions between genes and environmental factors in asthma and atopy: new developments

Asthma and associated phenotypes are complex traits most probably caused by an interaction of multiple disease susceptibility genes and environmental factors. Major achievements have occurred in identifying chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma, atopic dermatitis, IgE levels and response to asthma therapy. The aims of this review are to explain the methodology of genetic studies of multifactorial diseases, to summarize chromosomal regions and polymorphisms in candidate genes linked to or associated with asthma and associated traits, to list genetic alterations that may alter response to asthma therapy, and to outline genetic factors that may render individuals more susceptible to asthma and atopy due to environmental changes.     

Genome-wide multilocus analysis for immune-mediated complex diseases

In postgenomic era, searching and identification of disease genes associated with complex diseases are still one of the great challenge for dissecting human complex diseases. To improve the disease gene localization for complex diseases, a group of closely immune-mediated disease loci were overlapped on each chromosome based on previously reported genome-wide scanning data. Interestingly, five overlapping chromosomal regions (1q21, 2q33, 5q31.1-q33.1, 6p21, and 11q13) were identified by co-localizing disease loci for the following diseases: diabetes, asthma, atopic dermatitis, osteoporosis, and inflammatory bowel disease. The development of specific disease was associated with different combinations of disease loci among five overlapped chromosomal regions. Therefore, the analysis of multiple genetic loci should be considered to determine the effects of multiple genes responsible for complex diseases resulting from the influence of multiple genes.     

Genetically programmed differences in epidermal host defense between psoriasis and atopic dermatitis patients

In the past decades, chronic inflammatory diseases such as psoriasis, atopic dermatitis, asthma, Crohn's disease and celiac disease were generally regarded as immune-mediated conditions involving activated T-cells and proinflammatory cytokines produced by these cells. This paradigm has recently been challenged by the finding that mutations and polymorphisms in epithelium-expressed genes involved in physical barrier function or innate immunity, are risk factors of these conditions. We used a functional genomics approach to analyze cultured keratinocytes from patients with psoriasis or atopic dermatitis and healthy controls. First passage primary cells derived from non-lesional skin were stimulated with pro-inflammatory cytokines, and expression of a panel of 55 genes associated with epidermal differentiation and cutaneous inflammation was measured by quantitative PCR. A subset of these genes was analyzed at the protein level. Using cluster analysis and multivariate analysis of variance we identified groups of genes that were differentially expressed, and could, depending on the stimulus, provide a disease-specific gene expression signature. We found particularly large differences in expression levels of innate immunity genes between keratinocytes from psoriasis patients and atopic dermatitis patients. Our findings indicate that cell-autonomous differences exist between cultured keratinocytes of psoriasis and atopic dermatitis patients, which we interpret to be genetically determined. We hypothesize that polymorphisms of innate immunity genes both with signaling and effector functions are coadapted, each with balancing advantages and disadvantages. In the case of psoriasis, high expression levels of antimicrobial proteins genes putatively confer increased protection against microbial infection, but the biological cost could be a beneficial system gone awry, leading to overt inflammatory disease.     

Old drugs,new tricks: Emerging role of drug repurposing in the management of atopic dermatitis

Atopic dermatitis is a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators which lead to dry, thickened, cracked, scaly skin. The current treatment options for atopic dermatitis management comprise drawbacks and leave unmet effective clinical needs. So, the approach for repurposing existing drugs for atopic dermatitis management may potentially overcome these unmet needs. Diseases that share the common pathophysiological pathways with atopic dermatitis can serve as a foundation for the repurposing of drugs. Drugs used in the management of cancer, rheumatoid arthritis, and other immune-mediated diseases such as psoriasis are under investigation to know the potential in atopic dermatitis management by utilizing repurposing strategies for a novel therapeutic indication. This review mainly envisages the probable repurposing of drugs for the management of atopic dermatitis disease; the barriers and regulatory aspects involved in the repurposing of existing drugs.     

The filaggrin story: novel insights into skin-barrier function and disease

Recent reports have uncovered the key role of the protein filaggrin in maintaining an effective skin barrier against the external environment. Loss-of-function mutations in the profilaggrin gene (FLG) are common and are present in up to 10% of the population. These mutations are the cause of the semi-dominant skin-scaling disorder ichthyosis vulgaris and are a major risk factor for the development of atopic dermatitis. The discovery of these mutations also provides new data concerning the genetics of atopic asthma as well as intriguing insight into disease mechanisms of systemic allergies involving antigen exposure in skin with defective barrier function. Collectively, these novel findings have significant implications for the classification and future clinical management of patients with atopic and allergic diseases.     

Role of dysregulated apoptosis in atopic dermatitis

Atopic dermatitis is a chronic inflammatory skin disease with a complex immune dysregulation and interplay of genetic, environmental and psychological factors. Activation and skin-selective homing of peripherial-blood T cells, and effector functions in the skin, represent sequential events in the pathogenesis. Dysregulated apoptosis in skin-homing T cells, eosinophils and keratino-cytes contributes to the elicitation and persistence of atopic derrmatitis.     

Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21–22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.     

Replication of genome-wide association studies on asthma and allergic diseases in Korean adult population

Allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis are heterogeneous diseases characterized by multiple symptoms and phenotypes. Recent advancements in genetic study enabled us to identify disease associated genetic factors. Numerous genome-wide association studies (GWAS) have revealed multiple associated loci for allergic diseases. However, the majority of previous studies have been conducted in populations of European ancestry. Moreover, the associations of single nucleotide polymorphisms (SNPs) with allergic diseases have not been studied amongst the large-scale general Korean population. Herein, we performed the replication study to validate the previous variants, known to be associated with allergic diseases, in the Korean population. In this study, we categorized three allergic related phenotypes, one allergy and two asthma related phenotypes, based on self-reports of physician diagnosis and their symptoms from 8,842 samples. As a result, we found nominally significant associations of 6 SNPs with at least one allergic related phenotype in the Korean population.     

Association of polymorphisms in the toll-like receptor genes with atopic dermatitis in the Republic of Bashkortostan

Atopic dermatitis is a common chronic inflammatory skin disease and depends on the interaction between environmental factors and genetic predisposition. A considerable role in allergic disorders is played by polymorphisms of the genes of pattern recognition receptors (PRRs), which recognize conserved standard molecular structures (patterns) unique to large pathogen groups. Polymorphisms of several PRR genes, including the genes of Toll-like receptors (TLR1, TLR2, TLR4, TLR5, TLR6, TLR9, and TLR10), NOD-like receptors (NOD1 and NOD2), and a lipopolysaccharide receptor (CD14) along with C11orf30 and LRRC32 from chromosome 11q13.5, were studied in atopic dermatitis patients and control subjects from Bashkortostan. TLR1 (rs5743571 and rs5743604), TLR6 (rs5743794), and TLR10 (rs11466617) polymorphisms were associated with atopic dermatitis. The results supported the idea that innate immunity and polymorphisms of the TLR2-family genes play a substantial role in atopic dermatitis.     

Association of the Late Cornified Envelope-3 Genes with Psoriasis and Psoriatic Arthritis:A Systematic Review

Psoriasis(Ps)and psoriatic arthritis(Ps A)are genetically complex diseases with strong genetic evidence.Recently,susceptibility genes for Ps and Ps A have been identified within the late cornified envelop(LCE)gene cluster,especially the cluster 3(LCE3)genes.It is noteworthy that the deletion of LCE3B and LCE3C(LCE3C_LCE3B-del)is significantly associated with these two diseases.Gene-gene interactions between LCE3 genes and other genes are associated with Ps and Ps A.LCE3 genes also have pleiotropic effect on some autoimmune diseases,such as rheumatoid arthritis,atopic dermatitis and systemic lupus erythematosus.Further studies need to focus on the potential function of LCE3 genes in the pathogenesis of Ps and Ps A in the future.     

The human genome project--some implications of extensive "reverse genetic" medicine

Impressive progress has been made during the past several decades in understanding the pathogenesis of human genetic disease. The tools of molecular biology have allowed the isolation of many disease-related genes by forward and a few by reverse genetics, and the imminent completion of a complete human genetic linkage map will accelerate the genetic characterization of many more genetic diseases. The major impacts of the molecular characterization of human genetic diseases will be 1. To increase markedly the number of human diseases that we recognize to have major genetic components. We already understand that genetic diseases are not rare medical curiosities with negligible societal impact, but rather constitute a wide spectrum of both rare and extremely common diseases responsible for an immense amount of suffering in all human societies. The characterization of the human genome will lead to the identification of genetic factors in many more human diseases, even those that now seem too multifactorial or polygenic for ready understanding. 2. To allow the development of powerful new approaches to diagnosis, detection, screening and even therapy of these disorders aimed directly at the mutant genes rather than at the gene products. This should eventually allow much more accurate and specific management of human genetic disease and the genetic factors in many human maladies. The preparation of a fine-structure physical map of the entire human genome together with an overlapping contiguous set of clones spanning entire chromosomes or large portions of chromosomes is rapidly becoming feasible, and the information that will flow from this effort promises eventually to affect the management of many important genetic diseases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Model-based clustering of binary longitudinal atopic dermatitis disease histories by latent class mixture models

Atopic dermatitis is a skin disease which affects mainly children, has a very strong genetical component, and manifests itself clinically as flexural excema in connection with torturing itching. The course of disease is notoriously changeable and runs in phases, therefore it is difficult to predict the future course of disease. To improve prediction it would be interesting to identify clusters of children with different disease histories because this would shed light on common genetic and environmental risk factors. We use, relying on previous work of Nagin, a Latent class mixture model to estimate, in a data-dependent and model-based fashion, a clustering of typical binary atopic dermatitis disease histories in children. The data were collected from 1990 to 1997 in the so called MAS-study, a prospective cohort study of 1314 children in five German cities. The original method of Nagin is extended in two different aspects, first we use bootstrap confidence intervals to account for uncertainty in curve fitting, and second, we propose to model covariates for cluster membership by Anderson's Stereotype regression model. We feel that the Latent class mixture model is a valuable tool for assessing the course of atopic dermatitis, yielding a wealth of communicable and graphically displayable results.     

On the origins of Mendelian disease genes in man: the impact of gene duplication

Over 3,000 human diseases are known to be linked to heritable genetic variation, mapping to over 1,700 unique genes. Dating of the evolutionary age of these disease-associated genes has suggested that they have a tendency to be ancient, specifically coming into existence with early metazoa. The approach taken by past studies, however, assumes that the age of a disease is the same as the age of its common ancestor, ignoring the fundamental contribution of duplication events in the evolution of new genes and function. Here, we date both the common ancestor and the duplication history of known human disease-associated genes. We find that the majority of disease genes (80%) are genes that have been duplicated in their evolutionary history. Periods for which there are more disease-associated genes, for example, at the origins of bony vertebrates, are explained by the emergence of more genes at that time, and the majority of these are duplicates inferred to have arisen by whole-genome duplication. These relationships are similar for different disease types and the disease-associated gene's cellular function. This indicates that the emergence of duplication-associated diseases has been ongoing and approximately constant (relative to the retention of duplicate genes) throughout the evolution of life. This continued until approximately 390 Ma from which time relatively fewer novel genes came into existence on the human lineage, let alone disease genes. For single-copy genes associated with disease, we find that the numbers of disease genes decreases with recency. For the majority of duplicates, the disease-associated mutation is associated with just one of the duplicate copies. A universal explanation for heritable disease is, thus, that it is merely a by-product of the evolutionary process; the evolution of new genes (de novo or by duplication) results in the potential for new diseases to emerge.     

Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells

Skin protects the body from the environment and is an important component of the innate and adaptive immune systems. Atopic dermatitis and contact dermatitis are among the most frequent inflammatory skin diseases and are both determined by multigenic predisposition, environmental factors, and aberrant immune response. Peptidoglycan Recognition Proteins (Pglyrps) are expressed in the skin and we report here that they modulate sensitivity to experimentally-induced atopic dermatitis and contact dermatitis. Pglyrp3(-/-) and Pglyrp4(-/-) mice (but not Pglyrp2(-/-) mice) develop more severe oxazolone-induced atopic dermatitis than wild type (WT) mice. The common mechanism underlying this increased sensitivity of Pglyrp3(-/-) and Pglyrp4(-/-) mice to atopic dermatitis is reduced recruitment of Treg cells to the skin and enhanced production and activation Th17 cells in Pglyrp3(-/-) and Pglyrp4(-/-) mice, which results in more severe inflammation and keratinocyte proliferation. This mechanism is supported by decreased inflammation in Pglyrp3(-/-) mice following in vivo induction of Treg cells by vitamin D or after neutralization of IL-17. By contrast, Pglyrp1(-/-) mice develop less severe oxazolone-induced atopic dermatitis and also oxazolone-induced contact dermatitis than WT mice. Thus, Pglyrp3 and Pglyrp4 limit over-activation of Th17 cells by promoting accumulation of Treg cells at the site of chronic inflammation, which protects the skin from exaggerated inflammatory response to cell activators and allergens, whereas Pglyrp1 has an opposite pro-inflammatory effect in the skin.     

真菌与变态反应性皮肤病的相关性研究

真菌在自然界中分布广泛,部分是人体表面常驻的微生物之一。新近研究显示皮肤常驻真菌可通过影响皮肤屏障、调节皮肤免疫平衡和介导炎症反应等,在多种变态反应性疾病中起重要作用。本文就真菌与特应性皮炎、脂溢性皮炎、癣菌疹、荨麻疹等常见的变态反应性皮肤病的相关性研究进展作一综述,并介绍了国内外临床常见真菌变应原检测方法。     

Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families

Atopic dermatitis is a common skin disease frequently associated with allergic disorders such as allergic rhinitis and asthma. Controversial linkage findings between atopy and markers at chromosome 11q13 led us to search chromosome 11 for genes conferring susceptibility to atopic dermatitis and atopy. Twelve families were investigated using highly polymorphic markers and a powerful model-free linkage test. Two markers gave evidence for linkage, D11S903 (P = 0.02) and FCER1B (P = 0.005). A two-point lod-score analysis between these two markers revealed significant evidence for linkage (z _max = 4.02 at (θ = 0.0). In regard to model-dependent lod-score analyses between atopic disorders and FCER1B, two-point analysis gave a lod score of z = 0.78 whereas two-locus analysis using a recessive-dominant mode of inheritance displayed a significant lod score of z = 3.55. Only 2 of 12 families showed evidence for linkage using the latter oligogenic model. In conclusion, the results of our study map the FCER1B gene in close proximity to D11S903, support the finding of Cookson et al. implicating the IgE high-affinity receptor gene (FCER1B) at 11q13, and furthermore suggest an oligogenic mode of inheritance as well as heterogeneity in the genetic susceptibility to atopy and atopic dermatitis. Received: 6 November 1995 / Accepted: 1 October 1997     

Atopic dermatitis and birth factors: historical follow up by record linkage.

OBJECTIVE: To study if factors at birth are associated with later development of atopic dermatitis. DESIGN: Historical follow up by record linkage from Danish medical birth register. Children were followed up for 5.5 to 8.5 years. Second historical follow up study comprising questionnaire to mothers of singleborn children 6.5 to 9.5 years after birth. SETTING: Private dermatology clinics and dermatology and paediatric departments in the municipality of Aarhus, Denmark. SUBJECTS: 7862 singletons born in hospital between 1 January 1984 and 31 December 1986 to mothers living in the municipality of Aarhus. Questionnaires sent to 985 mothers. MAIN OUTCOME MEASURES: Gestational age, birth weight, parity, and age of mother at the time of birth. Atopy in children diagnosed by specialists in dermatology and physicians. Family size; diagnosis of atopic dermatitis, allergic rhinitis, and asthma; family predisposition; and mothers'' smoking habits during pregnancy determined from questionnaires. RESULTS: Of 7862 children, 403 were diagnosed as having atopic dermatitis by a specialist; the cumulative incidence at age 7 was 5.6%. High gestational age and low parity were associated with an increased risk of atopic dermatitis. Among 985 children atopic dermatitis had been diagnosed by any physician in 184; the cumulative incidence at age 7 was 18.7%. High birth weight, high gestational age, and family history of atopy were associated with increased risk of atopic dermatitis. CONCLUSION: In both studies the incidence of atopic dermatitis was associated with high gestational age and in one with high birth weight also. The causes for these associations are at present unknown but may indicate that even during gestation factors associated with atopic dermatitis influence maturation.