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Gene-Environment Interactions in Chronic Inflammatory Disease

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Gene-Environment Interactions in Chronic Inflammatory Disease commentarY Gene-environment interactions in chronic inflammatory disease Harald Renz, Erika von Mutius, Per Brandtzaeg, William O Cookson, Ingo B Autenrieth & Dirk Haller Chronic inflammatory diseases represent a major challenge for both clinical research and patient care, and evidence indicates that these disorders develop as a result of complex gene-environment interactions. Better understanding of their cause-and-effect relationship is the basis for emerging proposals for therapy and prevention. ince the end of World War II there has been The European Science Foundation brought polymorphisms, which has shown that there Sa substantial increase in the incidence of together an international group of experts on are overlapping susceptibility genes in these chronic inflammatory disease that seems to fol- subjects ranging from epidemiology to epigenet- inflammatory disorders3. A prototypic example low a geographical pattern of industrialization ics for a 5-day meeting (19–22 October 2010) in is the discovery of polymorphisms in ORMDL3 and urban living1. This includes allergic condi- Barcelona, Spain2, intended to help define stra- in both asthma and IBD4,5. tions (asthma, allergic rhinoconjunctivitis, food tegic directions for research into this increasing Despite the identification of many potential allergies and eczema), as well as autoimmune public health concern. In this first meeting of the susceptibility genes6,7, their individual effects disorders such as type 1 diabetes, chronic inflam- Forward Look initiative of the European Science seem to be quite modest. Thus, for many dis- matory bowl disease (IBD) and neurodegenera- Foundation, discussions focused on the grand eases, the alleles that have been identified by tive disease. Genetics cannot account for the challenges that face research into gene-envi- genome-wide association studies explain only increase in prevalence over time (Fig. 1a), but ronment interactions in metabolic and immune a very small proportion of disease heritability epidemiological evidence supports the idea of a system–mediated pathologies with inflamma- for both IBD and asthma. Similar observations Nature America, Inc. All rights reserved. All rights Inc. America, Nature combination of environmental and genetic risk tory processes as the key driver of disease initia- have been made for type 1 diabetes, for which 1 1 factors. The nature of these risk factors and the tion and/or perpetuation. Surprisingly, diseases the most common polymorphisms explain less pathogenic mechanisms involved, however, are as diverse at the phenotype level as obesity and than 30% of heritable risk8,9, and even in identi- © 20 only just beginning to be understood (Fig. 1b). asthma share similarities at the molecular and cal twins, a concordance of only about 50% has cellular levels. Such striking findings shed new been observed. The situation in type 2 diabetes light on this area and triggered the organiza- is even more striking10. Having a first-degree Harald Renz is with the Institute of Laboratory tion of an interdisciplinary European Science relative with type 2 diabetes is associated with a Medicine and Pathobiochemistry, Molecular Foundation initiative. To structure this process, hazard ratio of between 3 and 4 for development Diagnostics, Philipps University, Marburg, Germany. the Barcelona meeting covered intrinsic and of the disease relative to that of people who do Erika von Mutius is with Dr. von Hauner Children’s extrinsic mechanisms of various chronic dis- not have affected relatives. Despite such distinct Hospital, Ludwig-Maximilians University Munich, eases together with emerging ideas in disease heritability, the susceptibility genes identified Germany. Per Brandtzaeg is with the Laboratory therapy and prevention. by genome-wide association studies account for for Immunohistochemistry and Immunopathology, only approximately 1% of the heredity of type Centre for Immune Regulation, University of Oslo, Intrinsic mechanisms 2 diabetes, making them essentially useless and the Department of Pathology, Oslo University The increasing incidence of chronic inflamma- for risk prediction11,12. Similar findings have Hospital, Rikshospitalet, Oslo, Norway. William tory disease such as diabetes, asthma, allergy been also obtained for other chronic inflam- O. Cookson is with the National Heart & Lung and IBD is widely considered to be due to a matory disease, including asthma and allergic Institute Imperial College London, United Kingdom. combination of environmental and individual eczema, which indicates the multigenicity and Ingo B. Autenrieth is with the Institute of Medical risk factors. Scientific findings have highlighted complexicity of these disorders. Thus, simple Microbiology and Hygiene, University Hospital similarities among these conditions at both the genetic explanations for individual susceptibil- Tübingen, Tübingen, Germany. Dirk Haller is with genetic level and mechanistic level. ity to chronic inflammatory disease have not the Section of Biofunctionality, Research Center The advent of genome-wide association been forthcoming. for Nutrition and Food Science, and Center for Diet studies raised the hope that disease risk could Such findings highlight a key challenge in and Disease, Technical University Munich, Munich, be stratified according to individual suscepti- defining the genetic factors that determine dis- Germany. bility alleles. Such efforts have resulted in the ease susceptibility in chronic inflammatory dis- e-mail: [email protected] identification of several disease-associated ease; that is, the failure of single alleles or even NATURE IMMUNOLOGY VOLUME 12 NUMBER 4 APRIL 2011 273 COMMENtaRY a b Susceptibility genes Organ or tissue-specific Cell type–specific Genotype Environmental microbiota Nutrition Barrier microbiome Phenotype Epigenetics Respiratory Gut mucosa mucosa Innate and Disease adaptive immunity Immunomaturation Immunoeducation Protection and Chronic tolerance inflammation interaction Mother-child Pre- or postnatal imprinting or postnatal Pre- Initiation Progression Remodeling Time Figure 1 A new paradigm for the development of chronic inflammation. The traditional simplistic paradigm of chronic inflammatory disease development (a) has been revised to a more complex understanding of the cornerstones of these conditions (b). In b, epigenetics (blue) represents a key mechanism linking genetic components (yellow) and the environment. Disease development depends on intimate interaction between intrinsic mechanisms (red) and extrinsic mechanisms (green) in a temporal and spatial way. allele combinations so far to facilitate distinct environmental stimulus leads to persistent and to obtain robust evidence that these signatures risk prediction. It is important to note, how- heritable epigenetic changes14. have a causal relationship with the pathogenesis ever, that the lack of distinct associations with A crucial element of epigenetic studies will be of the disease. As in genomic analyses, obtain- common single-nucleotide polymorphisms the generation of tissue- and cell type–specific ing an overview of epigenetic associations will does not mean that these genetic differences data. One example in which evidence has been require more detailed information on disease do not underlie susceptibility. Individual single- obtained for the epigenetic regulation of specific phenotype, including temporal changes from Nature America, Inc. All rights reserved. All rights Inc. America, Nature nucleotide polymorphisms with small effects cell types is in the differentiation of helper T initiation through to chronicity. 1 1 may together have metabolic consequences cells from naive CD4+ lymphocytes15,16. These A major focus for research into the cellular that can be used as biomarkers for risk strati- types of cells of the immune response are linked mechanisms that underlie chronic inflamma- © 20 fication. Sequencing technology has advanced to autoimmunity and allergy, and they may be tory disease is the tissue-environment inter- to such an extent that it can now be considered central to the development of disease chronicity face20. It is here, particularly in the mucosa trivial to analyze 1,500 single-nucleotide poly- through the generation of a long-lasting cellu- lining the gut and airways, that a careful balance morphisms at a time. The real challenge is the lar memory of earlier environmental exposures. must be maintained between host defense and ability to discern relevant patterns from the The extent of methylation of the promoter of uncontrolled unresolving inflammation. One data obtained. Furthermore, genetic variation the interferon-g gene has been identified as a area in which substantial advances have been is not only about single-nucleotide polymor- marker of commitment to the T helper type 1 made is in understanding the role of endoplas- 17 phisms. Other factors such as repetitive DNA (TH1) lineage . Thus, in a specific type of cell mic reticulum stress, autophagy and micro- elements or copy-number variants could also of the immune response, epigenetic changes can bial sensing in the pathogenesis of IBD21. The be involved, and these may be much more dif- determine important cell fate ‘decisions’ that unfolded protein response is a pathway from the ficult to address. are likely to influence disease18. Given those endoplasmic reticulum to the nucleus that pro- As risk alleles are very frequent in the healthy findings, epigenetic signatures might serve as tects cells from stress caused
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