Genetics Epigenetics and Asthma

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Without a doubt, genetics plays a role in the development of asthma. However, family and population studies show that asthma is a complex genetic disorder (Saltini et al. 1998). The genetic studies of asthma generally take one of two approaches: either phenotypic markers are used to search for asthma genes, or Human Leukocyte Antigen (HLA) genes are associated with responsiveness to specific proteins or peptide allergens. As noted in a review by Saltini and colleagues, the phenotypic markers most commonly used in the search for asthma gene(s) include: 1.) total serum IgE levels; 2.) immediate reactivity in skin tests to aeroallergens and specific IgE levels; 3.) bronchial hyperresponsiveness to physical and pharmacological stimuli; and 4.) a history of wheezing in the clinical diagnosis of asthma (Saltini et al. 1998). In that review, it was noted that the genetic loci tentatively associated with asthma are on chromosome 11q13 in close proximity to the IgE receptor, on chromosome 5q31 near a cytokine cluster comprising the IL-4, IL-5, and IL-13 genes, and near the beta-adrenergic receptor gene. These authors also reported that other studies do not confirm these findings (Sandford et al. 1996) and, in particular, linkage studies identify over a dozen genomic regions linked to asthma. In July 2002, Van Eerdewegh and colleagues reported finding a gene that is closely linked to bronchial hyperresponsiveness and asthma (2002). In that report, investigators analyzed the genomes of 460 families to link the ADAM33 gene to increased asthma susceptibility. ADAM proteins are membrane-anchored metalloproteases with functions including the shedding of cell-surface cytokines and cytokine receptors.

The second approach to establishing a genetic association with asthma emphasizes HLA molecules. Support for this approach comes from studies claiming a weak association of asthma with HLA-A1, B8, and DR3 (Apostolakis et al. 1996; Turner et al. 1977), but more studies are needed to confirm these associations. Narrowing the scope to defined allergens or to a type of asthma, i.e., occupational asthma, has helped define HLA associations. Moreover, it may be as likely in occupational asthma as in contact dermatitis that a subpopulation of exposed individuals with 'leaky" airways due to atopy or injured bronchial epithelium are more sensitive to environmental agents (Brooks 1992). Occupational asthma provides a model to test the hypothesis on susceptibility because of the diagnostic requirement for a causative agent to be identified. HLA genes appear to be directly linked to chemical susceptibility leading to occupational asthma; ultimately, HLA genes provide a genetic basis for this disease.

Lastly, if the forces influencing susceptibility to asthma are visualized as components of a Venn diagram, factors such as environment and molecular dys-regulation should not be solely supplemented by genetics per se. In light of information from recent reports, balancing an equation that fully integrates factors determining disease risk should include epigenetic factors (Figure 14.11). Defined as changes having no effect on the sequence of molecules that make up a genome, the study of epigenetics refers to the pattern of gene silencing and activation. Although every cell contains two copies of almost every gene, many genes in sperm and ova are biochemically altered to be silenced, or imprinted, throughout life. The potential relevance of epigenetics to the influence of perinatal toxicant exposure on asthma sensitization becomes clear when one considers recent data from experiments conducted in mice. In a report by researchers at Duke University (Waterland and Jirtle 2003), mice with identical genes for fur color displayed two different colors. The difference was that, in some mice, the gene for fur color had been silenced by what their mother ate during pregnancy. Because the genetic sequence remains the same, the changes associated with imprinting are epigenetic. Epigenetic changes are suspected of being at the root of fetal programming, which is the term applied when nutrition, and presumably exposure to environmental toxicants, during gestation seems to affect the risk of disease later in life. One example illustrating fetal programming as a result of epigenetic changes in imprinting involves children conceived by in vitro fertilization (IVF) who develop Beck-with-Wiedemann syndrome (BWS). In that disease, where the incidence is roughly six times higher than in non-IVF babies, a normally silenced gene (KCN10T) loses

Figure 14.11 The interplay of factors contributing to a susceptibility to asthma. An understanding of how environmental toxicants might affect components of the asthma sensitization engine in utero must derive from studies of more than genetics and the environment. In addition, elucidation of factors important in programming fetuses for susceptibility to asthmagenesis will likely involve studying dysregu-lation of many physiologic systems on a molecular scale, as well as epigenetic factors that affect genetic expression but do not change genomic sequences.

Figure 14.11 The interplay of factors contributing to a susceptibility to asthma. An understanding of how environmental toxicants might affect components of the asthma sensitization engine in utero must derive from studies of more than genetics and the environment. In addition, elucidation of factors important in programming fetuses for susceptibility to asthmagenesis will likely involve studying dysregu-lation of many physiologic systems on a molecular scale, as well as epigenetic factors that affect genetic expression but do not change genomic sequences.

its imprinting. The result is an increased production of a growth factor and an associated increase in childhood and adult cancers (Gicquel et al. 2003). Other examples of adult diseases known to be influenced by fetal perturbations include type II diabetes, hypertension, and coronary artery disease (reviewed in: Sallout and Walker 2003). Whether epigenetic phenomena influence the development of asthma remains to be studied.

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