The environment, epigenome, and asthma

doi:10.1016/j.jaci.2017.05.011

Journal of Allergy and Clinical Immunology

Volume 140, Issue 1, July 2017, Pages 14-23

https://doi.org/10.1016/j.jaci.2017.05.011 Get rights and content

Asthma prevalence has been on the increase, especially in North America compared with other continents. However, the prevalence of asthma differs worldwide, and in many countries the prevalence is stable or decreasing. This highlights the influence of environmental exposures, such as allergens, air pollution, and the environmental microbiome, on disease etiology and pathogenesis. The epigenome might provide the unifying mechanism that translates the influence of environmental exposures to changes in gene expression, respiratory epithelial function, and immune cell skewing that are hallmarks of asthma. In this review we will introduce the concept of the environmental epigenome in asthmatic patients, summarize previous publications of relevance to this field, and discuss future directions.

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 T_H2 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 PM_BC 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 T_H2 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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The epigenome is at the intersection of the environment, genotype, and cellular response. DNA methylation of cytosine nucleotides, the most studied epigenetic modification, has been systematically evaluated in human studies by using untargeted epigenome-wide association studies (EWASs) and shown to be both sensitive to environmental exposures and associated with allergic diseases. In this narrative review, we summarize findings from key EWASs previously conducted on this topic; interpret results from recent studies; and discuss the strengths, challenges, and opportunities regarding epigenetics research on the environment-allergy relationship. The majority of these EWASs have systematically investigated select environmental exposures during the prenatal and early childhood periods and allergy-associated epigenetic changes in leukocyte-isolated DNA and more recently in nasal cells. Overall, many studies have found consistent DNA methylation associations across cohorts for certain exposures, such as smoking (eg, aryl hydrocarbon receptor repressor gene [AHRR] gene), and allergic diseases (eg, EPX gene). We recommend the integration of both environmental exposures and allergy or asthma within long-term prospective designs to strengthen causality as well as biomarker development. Future studies should collect paired target tissues to examine compartment-specific epigenetic responses, incorporate genetic influences in DNA methylation (methylation quantitative trait locus), replicate findings across diverse populations, and carefully interpret epigenetic signatures from bulk, target tissue or isolated cells.
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Allergic inflammation and airway remodeling frequently occur in asthma. This study clarifies a novel LINC1810064F22Rik-mediated ceRNA mechanism involved in asthma-induced allergic inflammation and airway remodeling based on bioinformatics analysis and in vivo and in vitro experiments. The differentially expressed lncRNAs and downstream effectors were predicted in silico. The targeting relationship among LINC1810064F22Rik, miR-206-5p, and HDAC4 was predicted by bioinformatics analysis, which was further validated by dual luciferase reporter gene assay. The asthma-like airway inflammation was induced in mice using ovalbumin (OVA) sensitization/challenge with immune adjuvant Al(OH)₃, while alveolar epithelial cells (AECs) were exposed to IL-33 to mimic in vitro inflammatory environment. LINC1810064F22Rik and HDAC4 were highly expressed, while miR-206-5p was poorly expressed in the tracheal tissues of OVA mice and the IL-33-treated AECs. The OVA mice and IL-33-treated AECs were subjected to gain- or loss-of-function experiments to detect the interaction of LINC1810064F22Rik/miR-206-5p/HDAC4 axis and their effects on allergic inflammation and airway remodeling. LINC1810064F22Rik competitively bound to miR-206-5p, and miR-206-5p targeted and inhibited HDAC4. The in vivo animal experiments indicated that LINC1810064F22Rik promoted asthma-induced allergic inflammation and airway remodeling by sequestering miR-206-5p away from HDAC4. The evidence provided by our study highlighted the involvement of the LINC1810064F22Rik/miR-206-5p/HDAC4 axis in facilitating allergic airway inflammation and airway remodeling in OVA mice.
Genome-wide DNA methylation profiling after Ayurveda intervention to bronchial asthmatics identifies differential methylation in several transcription factors with immune process related function
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The Indian traditional medicinal system, Ayurveda, describes several lifestyle practices, processes and medicines as an intervention to treat asthma. Rasayana therapy is one of them and although these treatment modules show improvement in bronchial asthma, their mechanism of action, particularly the effect on DNA methylation, is largely understudied.
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Our study reports the DNA methylation-regulated genes in bronchial asthmatics showing improvement in symptoms after Ayurveda intervention. DNA methylation regulation in the identified genes and pathways represents the Ayurveda intervention responsive genes and may be further explored as diagnostic, prognostic, and therapeutic biomarkers for bronchial asthma in peripheral blood.
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Asthma is a complex disease with significant genetic and environmental contributions to risk, and substantial heterogeneity with respect to the age of onset, associated comorbidities, severity, and response to drugs, among others. Genome-wide association studies (GWASs) of asthma have been successful in identifying common variants with small effects on risk, highlighting at least 150 independent loci. Yet, the proportion of genetic variance explained by GWAS variants remains small, suggesting that future studies should both focus on more homogeneous subtypes, or endotypes, of asthma and consider other genetic mechanisms that could impact asthma risk. In this chapter, we will review the successes and limitations of asthma GWASs, alternative genetic approaches such as rare variant analysis, and epigenomics as the bridge between the environment and risk for asthma. Finally, we will discuss outstanding questions and future directions for more fully characterizing the genetic architecture of asthma.
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This study examines how asthma and other chronic obstructive lung diseases vary in different regions. Information pertaining influence of region as a proxy for the environment on asthma is not well established, yet important for healthcare, travel, and migration decisions. The study was based on data collected from the Oman Ministry of Health’s annual reports from 2010 to 2019. Incidence rates for eleven regions in the Sultanate of Oman were analyzed using statistical tools, including; analysis of variance and the logistic regression model to determine the effect of region on asthma and other chronic obstructive lung diseases. Overall, the incident rates differed significantly by region, implying a potential environmental difference. There was no significant variation by year. Over the ten years, the incidence rates stagnated between 250 and 300 per 10000 of the population but showed a decreasing trend between 2016 and 2019. The regression model shows that all other regions had significantly increased odd ratios compared to the Muscat region. In addition, five asthma-region classifications were identified from our analysis. Therefore, there is significant evidence of regional variation in the incidence of asthma and other chronic obstructive lung diseases. This confirmation of regional differences could imply differences in environmental characteristics. This study’s findings may guide decision-making toward managing asthma and chronic obstructive lung diseases.
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Glyphosate (N-(phosphonomethyl)glycine) is a broad-spectrum systemic herbicide and crop desiccant. Glyphosate has long been suspected of leading to the development of cancer and of compromising fertility. Herbicides have been increasingly recognized as epigenetic modifiers, and the impact of glyphosate on human and animal health might be mediated by epigenetic modifications. This article presents the results from an animal study where pigs were exposed to glyphosate while feeding. The experimental setup included a control group with no glyphosate added to the feed and two groups of pigs with 20 ppm and 200 ppm of glyphosate added to the feed, respectively. After exposure, the pigs were dissected, and tissues of the small intestine, liver, and kidney were used for DNA methylation and gene expression analyses. No significant change in global DNA methylation was found in the small intestine, kidney, or liver. Methylation status was determined for selected genes involved in various functions such as DNA repair and immune defense. In a CpG island of the promoter for IL18, we observed significantly reduced DNA methylation for certain individual CpG positions. However, this change in DNA methylation had no influence on IL18 mRNA expression. The expression of the DNA methylation enzymes DNMT1, DNMT3A, and DNMT3B was measured in the small intestine, kidney, and liver of pigs exposed to glyphosate. No significant changes in relative gene expression were found for these enzymes following dietary exposure to 20 and 200 ppm glyphosate. In contrast, a significant increase in expression of the enzyme TET3, responsible for demethylation, was observed in kidneys exposed to 200 ppm glyphosate.

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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.

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Reviews and feature articleThe environment, epigenome, and asthma

Section snippets

Etiology of asthma

Allergens and asthma

Air pollution and microbial factors and the severity of asthma

Introduction to epigenetics

Environment and the epigenome

Asthma epigenetics

Nasal epithelium as a biosensor of the environment with relevance to the disease process

Epigenetic changes associated with exposure to air pollution

Epigenetic changes associated with exposure and sensitization to allergens

Epigenetic changes and the microbiome

Future perspective

Allergol Immunopathol (Madr)

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Lancet

Respir Physiol

Chest

Respir Med

J Allergy Clin Immunol

Lancet

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Toxicol Appl Pharmacol

J Allergy Clin Immunol

J Allergy Clin Immunol

Cell Host Microbe

J Allergy Clin Immunol

Curr Opin Immunol

J Allergy Clin Immunol

Immunity

J Biol Chem

Immunity

Variants of DENND1B associated with asthma in children

N Engl J Med

Discovering susceptibility genes for asthma and allergy

Nat Rev Immunol

The genetics of asthma and allergic disorders

Discov Med

The genetics of asthma. Maternal effects in atopic disease

Clin Exp Allergy

Gene polymorphism in Netherton and common atopic disease

Nat Genet

The many paths to asthma: phenotype shaped by innate and adaptive immunity

Nat Immunol

Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study

N Engl J Med

Effect of 17q21 variants and smoking exposure in early-onset asthma

N Engl J Med

Occupational asthma

N Engl J Med

Epidemiologic approaches for assessing health risks from complex mixtures in indoor air

Environ Health Perspect

Virus-induced airway hyperresponsiveness and asthma

Am J Respir Crit Care Med

The inverse association between tuberculin responses and atopic disorder

Science

Maternal Nrf2 and gluthathione-S-transferase polymorphisms do not modify associations of prenatal tobacco smoke exposure with asthma and lung function in school-aged children

Thorax

Intrauterine effects of maternal smoking on sensitization, asthma, and chronic obstructive pulmonary disease

Proc Am Thorac Soc

Air pollutant effects on fetal and early postnatal development

Birth Defects Res C Embryo Today

Effect of early life exposure to air pollution on development of childhood asthma

Environ Health Perspect

Mothers' dietary patterns during pregnancy and risk of asthma symptoms in children at 3 years

Ir Med J

Functions of T cells in asthma: more than just T(H)2 cells

Nat Rev Immunol

Asthma genetics and intermediate phenotypes: a review from twin studies

Twin Res

Multivariate genetic analysis of atopy phenotypes in a selected sample of twins

Clin Exp Allergy

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

Nature

A large-scale, consortium-based genomewide association study of asthma

Reviews and feature article
The environment, epigenome, and asthma