Mapping susceptibility genes for asthma and allergy

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1 Mapping susceptibility genes for asthma and allergy Timothy D. Howard, PhD, Deborah A. Meyers, PhD, and Eugene R. Bleecker, MD Baltimore, Md Allergy and asthma are related conditions caused by a complex interaction of genetic factors and environmental influences. With family data from several different populations, linkage analysis has been performed and used to identify regions of the genome that contain susceptibility genes for these conditions. To date, 4 genome screens have been completed and have successfully identified several chromosomal locations that are likely to contain asthma and allergy genes. Many of these regions contain potential biologic candidate genes that modulate immunologic responses or airways inflammation. By focusing on the common regions that have been replicated in these 4 genome screens, the major susceptibility genes for asthma and allergy should be identified. This will lead to an improved understanding of pathogenic factors that lead to development or progression of asthma and allergic diseases. (J Allergy Clin Immunol 2000;105:S477-81) Key words: Asthma, allergy, genome screens, candidate genes Asthma is a common respiratory disease caused by bronchial inflammation, characterized by intermittent airways obstruction and respiratory symptoms. Bronchial hyperresponsiveness () and total serum IgE levels, characteristic findings in asthma, have been shown to have a strong genetic component. Understanding the genetic mechanisms responsible for allergy and asthma will provide a better understanding of the pathogenesis of asthma and new diagnostic approaches that may lead to improved preventive measures. Thus asthma is a complex genetic disease, the development of which is determined by the interaction between host susceptibility and environmental exposures. It is possible that gene-environment interactions initially cause presymptomatic states in susceptible individuals before symptomatic disease is produced (Fig 1). The presence of atopy or may characterize these presymptomatic states. 1,2 Genetic factors may also interact with ongoing environmental exposures to modulate disease expression (severity). Understanding gene-environment interactions in asthma and allergy may lead to therapeutic interventions for asthma that prevent disease progression and the development of irreversible changes in airway function. From the Center for the Genetics of Asthma and Complex Diseases, University of Maryland, Baltimore. Supported by National Institutes of Health grants R01-HL48341 and U01- HL Reprint requests: Eugene R. Bleecker, MD, Center for the Genetics of Asthma & Complex Diseases, University of Maryland, 108 N Greene St, Suite 119, Baltimore, MD Copyright 2000 by Mosby, Inc /2000 $ /0/ Abbreviations used : Bronchial hyperresponsiveness IgE: Immunoglobulin E EOS: Eosinophil count IL: Interleukin HLA: Human leukocyte associated antigen NOS: Nitric oxide synthase IFN-γ: Interferon gamma Two approaches are commonly used to identify susceptibility genes for a disease. First, candidate genes may be evaluated when obvious candidates play critical functions in the onset or progression of a disease. With complex diseases such as asthma and allergy, however, this approach quickly results in the evaluation of a very large number of potential candidates. Therefore candidate gene analysis is most useful in populations where family information is not available (eg, case-control studies) or when specific biologic or positional candidates (localized from linkage studies) are available. The second approach for identifying susceptibility genes is a genome-wide screen. The results of 4 genome screens for asthma and/or closely associated phenotypes in 6 different population samples show evidence for linkage to multiple regions of the genome. Some of these regions show overlap between populations and are more likely to contain susceptibility genes for asthma and allergy. Many of these regions contain strong candidate genes based on localization with linkage approaches. In other regions no obvious candidate genes exist, and positional cloning studies using sequencing and identification of new genes will be necessary to identify the contributing genes. DEFINING PHENOTYPES IN ASTHMA AND ALLERGY Defining the phenotype is a central issue in identifying the genetic components of any complex disease. This definition is essential to identify the genes involved and the relationship between genetic and environmental influences. Although current definitions for asthma now emphasize the importance of inflammatory mechanisms in addition to physiologic changes associated with asthma, 3 often they are not helpful for early identification or for the differentiation of asthma from closely related conditions such as other obstructive airways diseases. A common approach may be to use a prior physician-based diagnosis of asthma, but recent studies show that this S477

2 S478 Howard et al J ALLERGY CLIN IMMUNOL FEBRUARY 2000 FIG 1. Gene-environment interactions in the development of childhood asthma. TABLE I. Chromosomal regions show evidence for linkage to different asthma and allergic phenotypes from 4 genome-wide screens Genome screen population Chromosome CSGA 6 Dutch 20,21 Australian 19 Hutterites 22 2q Asthma (Hispanic) Loose asthma 3p /asthma symptoms 3q 4q 5p Asthma (African American) 5q Asthma (Caucasian) Loose asthma 6p Asthma (Caucasian) IgE/EOS/atopy 7p IgE/EOS/ 9p 9q Loose asthma 10q IgE 11p Asthma (Caucasian) 11q IgE/skin test 12q Asthma (Caucasian/Hispanic) IgE Loose asthma 13q Asthma (Caucasian) Atopy 14q Asthma (Caucasian) 16q IgE/ 17p Asthma (African American) 17q IgE 19q Asthma (Caucasian) Strict asthma 21q Asthma (Hispanic) / strict asthma EOS, Eosinophil count. may result in underdiagnosis of asthma. 4 Allergy can be defined in a number of ways, typically by elevated total or specific serum IgE levels and/or positive skin tests to 1 or more allergens. These laboratory characteristics can be combined with the presence of respiratory symptoms (rhinitis or asthma) to comprise a clinical definition for allergic respiratory diseases. Because 1 uniform phenotype defining asthma or allergy does not exist, investiga-

3 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 2, PART 2 Howard et al S479 TABLE II. Candidate genes for asthma or atopy in selected regions of linkage Location Candidate gene Gene function 2q CD28 T-cell proliferation 3p Chemokine T-cell and macrophage recruitment cluster 5q IL-3 5,9,13 B-cell switching, proliferation of mast cells β2ar G protein coupled receptor in lung GRL Glucocorticoid receptor 6p21-p22 HLA region Antigen presentation TNF Mediation of inflammatory response 12q23 NOS Proinflammatory/bronchodilator IFNγ Inhibition of IL4 activity β2ar, β 2 -adrenergic receptor; GRL, glucocorticoid receptor; NOS, nitric oxide synthase. FIG 2. Overall approach to mapping asthma- and allergy-associated genes. tors have used subsets of the disease phenotype, often referred to as associated phenotypes. These phenotypes include the presence of, total and specific IgE levels, the presence of 1 or more positive skin tests, elevated eosinophils in blood or sputum, or combinations. 4-6 CANDIDATE GENE STUDIES Genetic studies have identified multiple chromosomal regions that may contain genes that contribute to asthma, atopy, or both. Evidence for linkage of high total serum IgE levels or atopy has been observed to chromosomes 5q, q, 9-11 and 12q. 12,13 These linkages were observed in Dutch, 7 English, 9 Afro-Caribbean, 13 Amish, 13 and German 12 populations. Each of these regions contains several important genes that are biologically relevant to IgE regulation (Table I). Regions of the genome that demonstrate evidence for linkage to also typically show evidence for linkage to elevated total serum IgE levels. On chromosome 5q, for example, evidence for the coinheritance of genes for atopy and was observed in an isolated Dutch population. 14 On chromosome 11q and 12q, either linkage or association of alleles from 2 markers separated by only a few centimorgans was observed with either log IgE or. 9,13 This finding is consistent with the clinical correlation observed between and elevated IgE levels GENOME SCREENS Four recent studies have contributed significantly to the mapping of allergy and asthma genes by conducting genome-wide screens in various human populations. 6,19-22 Families were recruited from Western Australia, 19 from the Netherlands, 20,21 3 ethnic groups within the United States (Caucasian, Hispanic, and African American), 6 and from the Hutterites, a religious sect from South Dakota. 22 The phenotypes studied include asthma,, elevated total serum IgE, and elevated serum eosinophil counts. Evidence for linkage to multiple chromosomal regions was reported in each study (Table II). The most interesting regions are those that show evidence for linkage by more than 1 group. Three regions were identified in 3 of the 4 studies. The replication of these regions in different populations indicates a strong likelihood that a gene responsible for asthma or allergy is located somewhere within these intervals. Other novel regions, identified in only 1 population or study, may represent false-positive results or may contain genes that are population specific. In either case, further mapping with additional genetic markers and families from the same population is necessary to fine-map the region to determine the reason for the evidence for linkage. CANDIDATE GENES WITHIN REPLICATED REGIONS Once a region with evidence for linkage has been replicated, the next step toward identifying the gene is to examine candidate genes within those regions. These candidates may play essential roles in the regulation of the immune response, such as IgE induction, or smooth muscle activity. Modification in the expression of these genes could significantly alter the IgE production pathway and lead to atopic phenotypes. IgE levels have also been strongly correlated with asthma and atopy. 15,23 Excellent candidates exist in regions that were identified in 1 or more linkage studies (Table II). CD28 on chromosome 2q is considered an accessory molecule in the regulation of IgE levels. 24 Antibodies that block CD28 can inhibit the synthesis of IgE. 25 The cytokine cluster on 5q contains numerous candidate genes for atopy, including IL-4, IL-5, IL-9, and IL-13. IL-4 is a key component in the induction of IgE production, and mouse models suggest that IL-4 may modulate airway responsiveness. Binding of IL-4 to its receptor is the first signal for the production of IgE after allergen exposure. Several polymorphisms have been reported in the IL- 4 receptor gene on chromosome 16. Recent studies show

4 S480 Howard et al J ALLERGY CLIN IMMUNOL FEBRUARY 2000 that these polymorphisms may be associated with IgE levels and atopic asthma A polymorphism at position 590 of the IL-4 promoter has been examined for association with asthma and atopy 30,31 with variable results. Rosenwasser and Borish 30 reported an association of the 590 alleles with asthma. However, this same variation was only marginally associated with specific IgE to house dust mite and to wheeze. 31 This region on chromosome 5q also contains the β 2 -adrenergic receptor, a target for the major bronchodilators used to treat asthma, and the glucocorticoid receptor. 32 Chromosome 6p contains the HLA region and TNF genes, which are important in antigen presentation and mediation of the inflammatory response, respectively. Chromosome 12q contains 2 candidate genes that could influence both atopy and hyperresponsiveness. The nitric oxide synthase gene is important in the inflammatory response and is also a bronchodilator. IFN-γ has multiple roles in modulating immune response, including inhibition of IL-4 activity. SUMMARY Genetic approaches will be useful in dissecting the complex genetic relationship between susceptibility to asthma and allergic disorders and environmental factors. Significant progress has been made in identifying regions of the genome that are linked to asthma and closely associated phenotypes (Fig 2). Moreover, recent findings suggest that genes may not only reflect a risk of the development of asthma but also modulate the expression or progression of asthma. It is important to note that genetic susceptibility to the development of asthma may require specific environmental exposures that are dependent on the genotype of a given patient. An important example of gene environment interactions is the response to pharmacologic agents that may be modified by an individual s genotype (pharmacogenetics). Four genome screens have provided numerous loci that contain potential candidate genes, especially in the regions that have been replicated in ethnically or geographically diverse populations. Additional linkage studies and positional cloning studies will further define the genes important in the regulation of asthma, allergic phenotypes, and. Better understanding of the genetic mechanisms that contribute to these phenotypes may lead to the identification of individuals at high risk for these conditions and potential customization of treatment regimens. REFERENCES 1. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyperreactivity. Am Rev Respir Dis 1980;121: Holgate ST, Beasley R, Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci 1987;73: US Public Health Service. Guidelines for the diagnosis and management of asthma; National Asthma Education and Prevention Program. US DHHS. (PHS). 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