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.     

Dendritic cells in intestinal immune regulation

A breakdown in intestinal homeostasis can result in chronic inflammatory diseases of the gut including inflammatory bowel disease, coeliac disease and allergy. Dendritic cells, through their ability to orchestrate protective immunity and immune tolerance in the host, have a key role in shaping the intestinal immune response. The mechanisms through which dendritic cells can respond to environmental cues in the intestine and select appropriate immune responses have until recently been poorly understood. Here, we review recent work that is beginning to identify factors responsible for intestinal conditioning of dendritic-cell function and the subsequent decision between tolerance and immunity in the intestine.     

Genetic aspects of Sjögren's syndrome

Sj?gren's syndrome is a multisystem inflammatory rheumatic disease that is classified into primary and secondary forms, with cardinal features in the eye (keratoconjunctivitis sicca) and mouth (xerostomia). The aetiology behind this autoimmune exocrinopathy is probably multifactorial and influenced by genetic as well as by environmental factors that are as yet unknown. A genetic predisposition to Sj?gren's syndrome has been suggested on the basis of familial aggregation, animal models and candidate gene association studies. Recent advances in molecular and genetic methodologies should further our understanding of this complex disease. The present review synthesizes the current state of genetics in Sj?gren's syndrome.     

Molecular aspects of rheumatoid arthritis: role of environmental factors

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease that affects 0.5-1% of the population. RA causes progressive joint destruction that leads to the restriction of activities of daily living and deterioration of quality of life. Although the pathogenesis of RA has not yet been fully elucidated, it is considered to be a complex, multifarious disease that is influenced by both genetic and environmental factors. Genetic influences that contribute to RA susceptibility have been demonstrated both in studies of twins and families, as well as in genome-wide linkage scans, and it is estimated that genetic factors are responsible for 50-60% of the risk of developing RA. Thus, environmental factors may explain the remaining risk of developing RA. A large variety of environmental factors such as infectious agents, smoking, sex hormones, pregnancy etc. have been extensively studied previously. Understanding of how these factors contribute to the development of RA may lead to the better understanding of pathogenesis of RA.     

Genetic aspects of Sjögren's syndrome

Sjögren's syndrome is a multisystem inflammatory rheumatic disease that is classified into primary and secondary forms, with cardinal features in the eye (keratoconjunctivitis sicca) and mouth (xerostomia). The aetiology behind this autoimmune exocrinopathy is probably multifactorial and influenced by genetic as well as by environmental factors that are as yet unknown. A genetic predisposition to Sjögren's syndrome has been suggested on the basis of familial aggregation, animal models and candidate gene association studies. Recent advances in molecular and genetic methodologies should further our understanding of this complex disease. The present review synthesizes the current state of genetics in Sjögren's syndrome.     

Models and mechanisms of metabolic regulation: genes, stress, and the HPA and HPG axes

A variety of models have been developed to better understand the mechanisms underlying individual variation in susceptibility to obesity. This review discusses several of these models and explores their role in understanding individual vulnerability to metabolic disease and the environmental factors around which metabolic perturbations occur. Recently, the focus of models has shifted towards heterogeneous populations, in which individuals characterized by a high vulnerability and individuals that are seemingly resistant can be identified. The use of these heterogeneous studies has lead to the identification of several novel biomarkers predicting obesity. This review therefore focuses on nontraditional factors, which are not directly implicated in metabolic regulation. First, the evidence from rodent knockout models for genetic factors involved in obesity is discussed. Second, the role of a stressful environment, particularly the early life environment is investigated along with a discussion of circadian disruption and metabolic disorders. Finally, the impact of sex-steroids, as exemplified by polycystic ovarian syndrome, is discussed. Overall, the data presented in our review demonstrate that in most cases interplay between genetic and environmental factors best predicts disease development. Our review shows that susceptibility to obesity may be explained by complex interactions between traditional homeostatic mechanisms, such as the hypothalamic peptide, and less studied mechanisms, like steroids and neurotrophic factors.     

Allergic asthma: influence of genetic and environmental factors

Allergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a "syndrome" resulting from a complex interplay between genetic and environmental factors. Worldwide, >300 million individuals are affected by this disease, and in the United States alone, it is estimated that >35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (T(H)2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in T(H)2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including T(H)2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention.     

Multiple sclerosis is not a disease of the immune system

Multiple sclerosis is a complex neurodegenerative disease, thought to arise through autoimmunity against antigens of the central nervous system. The autoimmunity hypothesis fails to explain why genetic and environmental risk factors linked to the disease in one population tend to be unimportant in other populations. Despite great advances in documenting the cell and molecular mechanisms underlying MS pathophysiology, the autoimmunity framework has also been unable to develop a comprehensive explanation of the etiology of the disease. I propose a new framework for understanding MS as a dysfunction of the metabolism of lipids. Specifically, the homeostasis of lipid metabolism collapses during acute-phase inflammatory response triggered by a pathogen, trauma, or stress, starting a feedback loop of increased oxidative stress, inflammatory response, and proliferation of cytoxic foam cells that cross the blood brain barrier and both catabolize myelin and prevent remyelination. Understanding MS as a chronic metabolic disorder illuminates four aspects of disease onset and progression: 1) its pathophysiology; 2) genetic susceptibility; 3) environmental and pathogen triggers; and 4) the skewed sex ratio of patients. It also suggests new avenues for treatment.     

Integrated analysis of genome-wide genetic and epigenetic association data for identification of disease mechanisms

Many human diseases are multifactorial, involving multiple genetic and environmental factors impacting on one or more biological pathways. Much of the environmental effect is believed to be mediated through epigenetic changes. Although many genome-wide genetic and epigenetic association studies have been conducted for different diseases and traits, it is still far from clear to what extent the genomic loci and biological pathways identified in the genetic and epigenetic studies are shared. There is also a lack of statistical tools to assess these important aspects of disease mechanisms. In the present study, we describe a protocol for the integrated analysis of genome-wide genetic and epigenetic data based on permutation of a sum statistic for the combined effects in a locus or pathway. The method was then applied to published type 1 diabetes (T1D) genome-wide- and epigenome-wide-association studies data to identify genomic loci and biological pathways that are associated with T1D genetically and epigenetically. Through combined analysis, novel loci and pathways were also identified, which could add to our understanding of disease mechanisms of T1D as well as complex diseases in general.     

Challenges and opportunities in genome-wide environmental interaction (GWEI) studies

The interest in performing gene-environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene-environment interaction studies and the technical challenges related to these studies-when the number of environmental or genetic risk factors is relatively small-has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze genome-wide environmental interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for genome-wide association gene-gene interaction studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to "joining" two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes.     

The genetics of Parkinson's disease

The effort to map the entire human genome has led recently to the important milestone publication in late 1999 of the complete sequence of chromosome 22. This has been facilitated by increasingly sophisticated tools for genetic analysis and the ensuing wealth of detailed genetic information. The quest for genetic factors contributing to Parkinson's disease and parkinsonian disorders has revealed a progressively complex picture implicating gene mutations in the rarer, autosomally inherited forms of Parkinson's disease and the interplay of genetic and/or environmental factors in the common sporadic forms of the disorder. These findings not only reiterate the complex genetic heterogeneity of Parkinson's disease but could also point towards common pathogenic mechanisms in Parkinson's disease and related neurodegenerative disorders.     

The emerging genetic architecture of type 2 diabetes

Type 2 diabetes is a genetically heterogeneous disease, with several relatively rare monogenic forms and a number of more common forms resulting from a complex interaction of genetic and environmental factors. Previous studies using a candidate gene approach, family linkage studies, and gene expression profiling uncovered a number of type 2 genes, but the genetic basis of common type 2 diabetes remained unknown. Recently, a new window has opened on defining potential type 2 diabetes genes through genome-wide SNP association studies of very large populations of individuals with diabetes. This review explores the pathway leading to discovery of these genetic effects, the impact of these genetic loci on diabetes risk, the potential mechanisms of action of the genes to alter glucose homeostasis, and the limitations of these studies in defining the role of genetics in this important disease.     

Genetic and environmental determinants of osteoporosis

Osteoporosis is a common, complex disease that is influenced by genetic and environmental factors. Although molecular genetic studies have identified several potential regions of linkage, underlying susceptibility gene(s) are largely unknown. Genetic susceptibility to osteoporosis may be both context dependent and developmentally regulated, and epigenetic mechanisms are the likely link between gene and environment. In this paper we will review the status of genetic research into osteoporosis, and present the evidence for gene-environment interaction in its pathogenesis. Finally, the current challenges and future directions of research will be briefly discussed.     

Genetics of Crohn disease, an archetypal inflammatory barrier disease

Chronic inflammatory disorders such as Crohn disease, atopic eczema, asthma and psoriasis are triggered by hitherto unknown environmental factors that function on the background of some polygenic susceptibility. Recent technological advances have allowed us to unravel the genetic aetiology of these and other complex diseases. Using Crohn disease as an example, we show how the discovery of susceptibility genes furthers our understanding of the underlying disease mechanisms and how it will, ultimately, give rise to new therapeutic developments. The long-term goal of such endeavours is to develop targeted prophylactic strategies. These will probably target the molecular interaction on the mucosal surface between the products of the genome and the microbial metagenome of a patient.     

Involvement of IL-1R/TLR signalling in experimental autoimmune encephalomyelitis and multiple sclerosis

Multiple sclerosis is a complex disease characterised by chronic inflammation, demyelination and axonal pathology resulting in progressive neurological disabilities. Multiple sclerosis is generally considered to be an autoimmune disease, even though the primary cause of the underlying autoimmune response is unknown. Epidemiological evidence suggests that both genetic and environmental factors play a key role in susceptibility to multiple sclerosis; however, the relative contributions of these factors in triggering the onset of the disease remain unclear. Several studies indicate that receptors belonging to the Interleukin-1 and Toll-like receptor families are crucially involved in the mechanisms underlying the development of experimental autoimmune encephalomyelitis, an animal model that mimics multiple sclerosis. Moreover, recent evidence highlights the importance of downstream signalling proteins in the Interleukin-1 and Toll-like receptor signalling pathways, namely, myeloid differentiation primary response protein 88 and Interleukin-1-receptor-associated kinase. This review summarises the current knowledge concerning the involvement of Interleukin-1/Toll-like receptor signalling in the development of experimental autoimmune encephalomyelitis and multiple sclerosis. A deeper understanding of the role of these important pathways in the pathogenesis of experimental autoimmune encephalomyelitis may eventually yield clinical benefits in the treatment of central nervous system-based inflammatory disorders.     

A polygenic basis for late-onset disease

The biological basis of late-onset disease has been shaped by genetic factors subject to varying degrees of evolutionary constraint. Late-onset traits are not only more sensitive to environmental variation, owing to the breakdown of homeostatic mechanisms, but they also show higher levels of genetic variation than traits directly influencing reproductive fitness. The origin and nature of this variation suggests that current strategies are poorly suited to identifying genes involved in many complex diseases.     

Using genomics for birth defects epidemiology: can epigenetics cut the GxE Gordian knot?

Most birth defects are etiologically complex disorders caused by combinations of genetic and environmental factors, but most studies of birth defect etiology have examined only genetic factors or only environmental factors and have not considered interactions among them. Genome-wide epigenetic studies, which use the same genomic technologies that have revolutionized our ability to identify genetic causes of disease, provide an attractive way to study gene-environment interactions. However, finding an association between epigenetic variation and an etiologically complex birth defect without knowledge of the genetic variation and environmental exposures affecting the individuals who were studied usually provides little or no information regarding the cause of the disorder. In order for genome-wide studies of epigenetic variation to contribute to our understanding of the causes of birth defects, these studies must be combined with studies of environmental exposures and studies of genetic variation in the same subjects. Under such circumstances, epigenetic studies may help to establish the molecular basis for gene-environment interactions.     

Molecular and genetic mechanisms of osteoporosis: implication for treatment

Osteoporosis is a leading public health problem in our rapidly growing, aging population. It is characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture risk. Osteoporosis is a complex multifactorial disease, determined by genetic and environmental factors as well as their interactions. A large number of molecular, genetic and environmental factors underlying osteoporosis have been identified in past decades. In this article, we review 1) the molecular mechanisms of several principal systemic and local factors regulating bone metabolism; and 2) the current status of genetic studies searching for genes underlying osteoporosis. Further, we attempt to integrate knowledge from those two fields, and their potential implications for osteoporosis treatment.