Reviews and feature articleThe environment, epigenome, and asthma
Section snippets
Etiology of asthma
Although inheritance,2, 3, 4, 5 parent-of-origin inheritance,6, 7, 8 the general environment,9, 10, 11, 12, 13, 14, 15, 16, 17 immunization,18 in utero exposures,19, 20, 21, 22, 23, 24 and TH2 immunity25 play important roles in the etiology of asthma, there is no unifying mechanism accounting for these etiologic events.
Asthma concordance in monozygotic twins is only approximately 50%,26 and the heritability of this disease is 0.40 to 0.85.27, 28 Initial genome-wide association studies (GWASs)
Allergens and asthma
Allergic sensitization is a critical risk factor for childhood asthma, conferring a 4- to 20-fold increase in the risk of having the disease.10, 35 Both indoor (molds, house dust mites, cockroaches, rodents, and pets) and outdoor (pollens from trees, grass, and weeds) allergens are critical environmental triggers of asthma.36, 37, 38 Seminal studies in this field have clearly demonstrated a role of the environment in asthma development. Exposure to house dust mite, cat, and dog allergen early
Air pollution and microbial factors and the severity of asthma
Air pollutants are known to exacerbate asthma symptoms and might also play a role in initiation of this disease.43, 44, 45 In most urban areas, and increasingly in suburban areas, components of traffic-related emissions are a major source of air pollution. However, air pollution represents a complex exposure with inorganic and organic components. Particulate matter (PM) carries both environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs) formed during incomplete combustion of
Introduction to epigenetics
Epigenetic mechanisms control expression levels of genes without changing DNA sequence. Hypermethylation of cytosines within CpG islands in gene promoters leads to gene silencing, and hypomethylation leads to active transcription.66, 67 More recent studies have demonstrated that methylation of less CpG-dense regions near islands (“shores”)68, 69 and within gene bodies70, 71 is also important in regulation of gene expression and alternative splicing and that the relationship between methylation
Environment and the epigenome
Although some of the epigenetic marks are heritable (eg, imprinted loci82) and genome-wide studies demonstrate a genetic component to interindividual variation in DNA methylation83, 84, 85, 86 and histone modification profiles,83, 84, 85 epigenetic marks are also strongly influenced by the environment.86 Epigenetic processes translate environmental exposures associated with disease risk into regulation of chromatin, which shapes the identity, gene expression profile, and activity of specific
Asthma epigenetics
Epigenetic mechanisms as a cause of asthma91 build on our current knowledge about the etiology of asthma: non-Mendelian3 and parent-of-origin inheritance,6 influence of direct9 and in utero92 exposures, and a strong component of immune regulation.25 Our early work in mice showed that in utero exposure to a high methyl donor diet resulted in an increase in airway inflammation (eosinophil recruitment and concentrations of IL-4 and IL-13), an increase in serum IgE levels, a skewing of the
Nasal epithelium as a biosensor of the environment with relevance to the disease process
The nasal and airway epithelium is the primary interface with the respirable environment; interacts with air pollution,43 allergens,112, 113, 114 and other environmental stimuli115; and directs airway inflammatory, immune, and regenerative responses to these exposures. Gene expression profiles of the asthmatic airway epithelium have identified genes associated with exposure to endotoxin,116 house dust mite allergen,116 cigarette smoke,117 asthma,117, 118 and disease subtypes.119 Importantly, it
Epigenetic changes associated with exposure to air pollution
Air pollution influences the peripheral blood epigenome in adults.124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135 Studies have shown that both short-term125, 127, 133 and long-term126, 129 exposures to PM affect DNA methylation, including genes of innate immunity (TLR4 and TLR2)125, 132 and asthma (HLA-DOB, HLA-DPA1, CCL11, CD40LG, ECP, FCER1A, FCER1G, IL9, IL10, IL13, and MBP).129 One study has also demonstrated the effect of PM10 and PMBC on 5-hydroxymethylcytosine.134 Similarly,
Epigenetic changes associated with exposure and sensitization to allergens
To date, very few studies have examined the relationship of allergen exposure and sensitization to changes in epigenetic marks. Sensitization to several allergens (tree, grass, house dust mite, and ragweed) has been associated with changes in DNA methylation in peripheral blood of older adults149 and in bronchial epithelial cells of adults in controlled exposure settings.144 CD4+ T cells isolated from ex vivo grass pollen extract–stimulated PBMCs of patients with seasonal allergic rhinitis have
Epigenetic changes and the microbiome
The microbiome represents the multitude of microbes (bacteria; archaea; microbial eukaryotes, such as fungi; and viruses) that live in the environment and that also inhabit our bodies. Exposure to a greater diversity or unique repertoire of microbes through bedding or household dust,64, 65, 154 birth by means of vaginal rather than cesarean section,155 or relatively restricted exposure to antibiotics in early life156, 157, 158 have all been associated with decreased incidence of childhood
Future perspective
A major goal of this field is to understand the complex interaction of the microbiome, indoor allergens, and air pollution with the dynamic biological responses in the nares that predispose to a TH2 phenotype and place subjects at risk of asthma (Fig 2). These environmental factors are likely to influence the epigenome differently based on genetic variants of the host. Thus far, isolated studies focused on genetics, epigenetics, pathobiology, and the microbiota have provided only a partial
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Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
Terms in boldface and italics are defined in the glossary on page 15.