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The Genetics of Atopy and Atopic Eczema
James A. MacLean, MD;
Frank J. Eidelman, MD
Arch Dermatol. 2001;137:1474-1476.
A genetic predisposition to the development of certain allergic diseases has been recognized since the early 1900s. In 1916, Cooke and van der Veer1 reported that almost 50% of patients with allergic rhinitis and asthma had a positive family history of similar illness. In 1923, Coca and Cooke2 coined the term atopy to describe immediate hypersensitivity reactions that had an inherited tendency. Their classification scheme was later criticized because of the mistaken belief that atopic diseases were transmitted in an autosomal dominant fashion. Coca and Cooke believed that reaginic (allergic) antibodies played a central role in disease pathogenesis, although they failed to recognize that these reactions were dependent on antigen-antibody interactions. Nonetheless, the term atopy has persisted in the medical literature and is often used synonymously with the terms allergy and immediate hypersensitivity. Consensus regarding a precise definition for atopy is lacking.3-4 Since the discovery of IgE and the elucidation of the mechanisms involved in immediate-type hypersensitivity reactions, most authors use the term to describe the inherited tendency to develop IgE antibodies to specific allergens. The inherited tendency to produce allergen-specific IgE predisposes individuals to the development of certain diseases, including asthma, allergic rhinitis, and atopic dermatitis.
The genetic predisposition to the development of asthma, allergic rhinitis, and atopic dermatitis has been confirmed by numerous epidemiological studies.5 The inheritance pattern of atopic disease is complex and does not follow classic Mendelian inheritance patterns. The development of these illnesses is dependent on a multiplicity of genes, and disease expression is influenced by environmental factors and exposures.6 The importance of environmental factors in the expression of allergic phenotypes has been emphasized lately with the epidemiological observation that the incidence of atopic illness is increasing in Westernized nations.7-9 The factors responsible for the increased incidence of allergic disease have not yet been completely elucidated, but most current hypotheses propose that changes in environmental factors have favored the expression of allergic disease in those who are genetically susceptible.
The study of complex genetic illnesses demands accurate definitions of the phenotypes being investigated.5 This has presented some problems for the study of atopic illnesses. The clinical definitions of atopic illnesses, such as asthma, allergic rhinitis, and atopic dermatitis, are necessarily broad to encompass the wide variation of disease expression that exists among individuals. Within these clinical phenotypes, however, are subtypes (eg, aspirin-sensitive asthma) in which the genetic determinants may be distinct from the group as a whole. If meaningful associations between genetic variability and disease expression are to be established for atopic illnesses, consideration must be given to the heterogeneous nature of these diseases. A second problem facing the study of atopic illness is the lack of definitive biological or physiological paraeters that are specific for these diseases. The use of quantifiable measurements such as bronchial hyperresponsiveness (as an asthma phenotype) is problematic because the genetic factors regulating bronchial hyperreactivity may be distinct from those that determine the clinical phenotype of asthma. Furthermore, a parameter like bronchial hyperreactivity may be present in individuals who do not have a clinical syndrome of asthma (eg, some patients with allergic rhinitis). The episodic nature of atopic illness and the important role that environmental factors play in disease expression also complicate the study of these illnesses from a genetic standpoint. Finally, the coexistence of more than 1 atopic illness in the same individual further complicates attempts to determine the genetic basis of these diseases. Segregating the genetic determinants of asthma, allergic rhinitis, and atopic dermatitis in populations that have comorbid disease will be difficult. For all these reasons, it is important for investigators studying the genetics of atopic illness to clearly delineate the phenotype(s) being investigated. Quantifiable markers in most studies examining the genetics of atopy have been total serum IgE level, presence of immediate skin reactivity to allergens, or presence of serologically measurable antigen-specific IgE. Atopic illnesses are usually defined using clinical criteria that have been determined by consensus.
Genetic research in atopic diseases has focused primarily on asthma, bronchial hyperresponsiveness, and elevated IgE level, with fewer studies examining atopic dermatitis and allergic rhinitis. We are likely to find that specific genes contribute to the development of each allergic disease (disease-associated genes), while other genes contribute to disease expression by modulating immune responses to favor the expression of the atopic state (atopy-associated genes).10 Examples of the latter would include the genetic tendency to develop immune responses that favor the development of allergic immune responses. For example, most CD4+ T cells found in allergic responses are of the TH2 phenotype.11 CD4+ TH2 cells secrete cytokines that favor the synthesis of IgE and the differentiation and maturation of eosinophils and mast cells. These humoral and cellular elements are central to the pathogenesis of allergic inflammatory states and the development of immediate hypersensitivity reactions. In contrast, CD4+ T cells of the TH1 phenotype secrete cytokines that favor the development of cell-mediated, delayed-type hypersensitivity responses.11 Individuals whose genes favor the development of TH2 polarized responses might be expected to be more prone to the development of atopic illness.
Different approaches have been used to study the role of genetic factors in the development of allergic disease. Epidemiological studies of populations, families, and twins have been helpful in elucidating the relative importance of genes and environment in the expression of allergic disease and in determining the transmission patterns of specific traits.5 Molecular strategies have focused on finding variants of particular genes and then determining if the variants are associated with disease expression (linkage analysis).12-13 Genome-wide screens have linked atopy with particular locations in the human genome, but which genes within these locations are influencing disease expression is unknown. Using this technique, researchers in the United Kingdom identified the first locus linked to atopy on the long arm of chromosome 11.14 Subsequent studies have discovered that the gene coding for the  subunit of the high-affinity Fc receptor for IgE (Fc RI) is located in this area. The high-affinity Fc receptor for IgE is expressed in cells involved in the allergic response, including mast cells and basophils. This receptor binds IgE to the surface of these cells and participates in cell activation when antigens cross-link the receptor-bound IgE antibodies. Whether variant expression of this gene is responsible for disease expression remains to be established. Several other genome-wide searches have linked more than a dozen chromosomal sites with atopy or atopic illnesses.10, 15 Many of these loci are in areas of the genome known to contain genes coding for proteins that are involved in host-immune responses (eg, interleukins and their receptors and major histocompatibility complex genes). While linkage analysis has discovered loci in proximity to immune response genes, organ-specific genes have yet to be identified.
Genome-wide linkage studies allow researchers to narrow the focus of attention to potential locations of disease-associated genes. An alternate strategy known as the "candidate region approach" examines specific regions of the genome where genes of potential interest are located. Examining a smaller area within the genome allows for more precise localization of variants—a process that could not be practically performed on the entire genome. This approach has been used to examine an area on chromosome 5, where a number of cytokine genes are clustered, and also on chromosome 6, where the genes coding for the major histocompatibility complex genes are located.12 The area of the genome being studied can be further narrowed by examining variants in specific genes that might be expected to play a role in influencing disease expression ("candidate gene approach").16
Atopic dermatitis is a chronic inflammatory disease of the skin that is often the earliest clinical presentation of atopic disease, preceding the development of allergy and/or asthma. Hanifin and Rajka17 defined specific diagnostic criteria for atopic dermatitis based on clinical features of the disease. These criteria have been modified but are still the basis for phenotype definition in genetic studies of atopic dermatitis.18 Genetic susceptibility to the development of atopic dermatitis has been confirmed in family and twin studies.19 Linkage analysis has revealed several genes that may contribute to the expression of atopic dermatitis (Table 1). Interestingly, the site originally identified as being linked to atopy (chromosome 11q13) has recently been linked specifically to atopic dermatitis.23 The gene coding for FcRI is located in this area. It should be noted that other studies have failed to confirm this association, and a role for genetic variants of the high-affinity receptor for IgE remains to be established.22 Atopic dermatitis has also been linked to chromosome 5q31.21-22 The genes coding for a number of different cytokines are located in this area (so-called interleukin gene cluster), including the TH2 cytokine interleukin 4. This loci has also been implicated in the genetic susceptibility to develop asthma.27 More recently, the gene for mast cell chymase (a serine protease present in cutaneous mast cells) has been linked to the genetic susceptibility for the development of atopic dermatitis.25 Loci in the vicinity of genes coding for T-cell surface molecules that are involved in T-cell costimulation and activation (CD80 and CD86) have also been linked to atopic dermatitis.20 The most recent studies have linked regions of the genome that correspond closely with loci that have previously been linked to psoriasis.26 Cookson et al26 raise the interesting possibility that the genetic susceptibility to atopic dermatitis may be influenced not only by genes for atopy, but also by genes with effects on dermal inflammation and immunity.
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Summary of Linkage Studies for Atopic Dermatitis
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Mapping the human genome will have an enormous impact on the care of the individual with atopic disease. Determining the genes responsible for specific atopic illnesses will improve our knowledge of disease pathogenesis and will thereby improve diagnosis and treatment. Identification of individuals at risk for atopic illness will be facilitated by the ability to screen for these genes at birth or even in utero. Because the phenotypic expression of atopic disease depends not only on a genetic contribution but also on environmental exposure, knowledge of disease susceptibility will allow early nonpharmacologic environmental interventions that may prevent disease. For example, an infant identified as being at risk for asthma would benefit from the institution of strict environmental precautions with regard to allergen exposure. Treatment with anti-inflammatory medications before symptoms occur is another intervention that may mitigate the effect of the inheritance of atopic genes.
Improved diagnostic classification of atopic diseases based on genotypic variants that identify subsets of atopy (eg, aspirin-sensitive patients with asthma) could help direct pharmacologic interventions by identifying individuals who would be more likely to respond to a particular treatment (eg, leukotriene receptor antagonists). Pharmacogenetic studies will address why some patients fail to respond to specific treatments, such as -agonists or corticosteroids. Understanding the genetic basis of atopic disease will also lead to the development of therapeutic interventions based on the genes primarily responsible for disease expression. This may lead us away from more generalized anti-inflammatory treatments (eg, steroids and other immunosuppressants) to more tailored immunomodulating agents (eg, TH2 cytokine antagonists). If, for example, the overproduction of a specific cytokine or set of cytokines is crucial in the early development of atopic dermatitis, then an obvious intervention with specific anticytokine therapy might abort the process before it starts. Elucidating the genetic basis of atopic illnesses may also improve conventional treatments for atopic disease, such as allergen immunotherapy. Genetic information may assist the identification of individuals who will be more likely to respond to allergen immunotherapy. Conventional immunotherapy may also be improved by the development of novel vaccines that inhibit allergic sensitization. Finally, a better understanding of the genetic basis of atopic disease may lead to the development of the ultimate therapy for genetic illness, that is, a specific gene therapy.28
AUTHOR INFORMATION
Accepted for publication July 24, 2001.
Corresponding author and reprints: James MacLean, MD, BUL 422, Massachusetts General Hospital, 50 Blossom St, Boston, MA 02114.
From the Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr MacLean); and the Department of Allergy and Immunology, Cleveland Clinic Florida, Fort Lauderdale (Dr Eidelman).
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