In an effort to identify genetic variants responsible for asthma, thousands of genetic studies have been performed. Of the potential answers to this dilemma, epigenetics represents a solution, according to a review published in Tuberculosis and Respiratory Diseases.

Familial clustering of asthmatics is indicative of a genetic component of asthma, a condition with up to 60% heritability. Over the last 3 decades, more than 100 loci have been identified as being linked with asthma, and recent genome-wide single nucleotide polymorphism (SNP) association studies have confirmed that SNPs on genes associated with antigen presentation, inflammation, and Th1/Th2 processes are “strongly associated” with asthma and its subphenotypes.

Worldwide asthma prevalence has increased over the past 30 years, but investigators note that changes in genetic variants of the disease have rarely occurred. They posit that exposure to changing exposomes — large sets of environmental exposures including diet, toxins, and hormones — have introduced “several different phenotypes of asthma.”

In 2007, epigenetics was defined via the following criteria: a change in the activity of a gene that does not involve a mutation; initiated by environment signals; and mitotically or meiotically inherited in the absence of the change in nucleotide sequence of genomic DNA. Epigenetic mechanisms include DNA CpG methylation, histone deformation, and non-coding RNA.

DNA methylation takes place in CpG occupying 1% of DNA bases in human somatic cells, resulting in a total number of CpG sites of approximately 28 million; 70% to 80% of the human DNA CpG bases are methylated. Considerable research has identified specific time periods during which individuals are more susceptible to the effects of environmental exposures and other asthma triggers, including during prenatal development, early childhood, and adolescence. Epigenetic modifications are more likely to develop during these times.

Both human skin and lungs have large surface areas exposed to external environments; surface area estimates depend on height, weight, and other factors. Both indoor and outdoor stimuli affect airway epithelium, with 2 methods that have been used to study DNA CpG methylation: candidate gene approaches and epigenome-wide association studies. One candidate CpG methylation approach utilized buccal mucosa of children with asthma on 1505 CpG loci across 807 genes, identifying a small number of DNA methylation signatures. Recent epigenome-wide association studies have been launched with the intention of searching for changes in global CpG methylations.

Many CpG methylation studies have relied on the use of DNA isolated from unfractionated peripheral blood leukocytes because they are widely available and easily accessed. New methods have been recently developed to infer the proportion of immune cell populations in these leukocytes using DNA methylation data. The major immunologic components of asthma pathogenesis and their epigenetic mechanisms specifically affect the expression of the transcription factors involved in the development of Th1, Th2, Th17, and regulatory T cells. Therefore, these DNA methylation profiles have been “very useful” in identifying the epigenetic change of immune status.

In terms of atmospheric environmental factors, smoking is the most important asthma risk factor. Through DNA damage and other mechanisms, cigarette smoke modulates gene expression; several epigenome-wide association studies have demonstrated that cigarette smoke results in global hypomethylation. In one study, smoke exposure was associated with a 2% increase in mean CpG methylation in the FERM domain containing 4A gene compared with no smoke exposure. Despite the potential for clinical relevance, the authors noted that the current interpretation of cross-sectional epigenetic studies is “problematic” because it is impossible to determine whether methylation alteration is a cause or consequence.

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Because DNA CpG methylation changes are more reversible than DNA mutations, “many treatment strategies are currently under investigation,” the authors wrote, including dietary manipulation, which has demonstrated that methyl-rich diets have been associated with epigenome hypermethylation. These findings have generated interest, but clinical efficacy is still unclear.

“Epigenetic influences and mechanisms have been clarified in allergic diseases and asthma, but there are still many questions to be solved yet,” the researchers posit. “The most complex situation is when both the gene and the environment are unknown.” Additional information on exposomes, they added, is necessary, and data should be analyzed via multi-Omnic approaches.

The researchers concluded that “If accurate influence and mechanisms of epigenetics are revealed, prevention and control strategies for asthma and its subtypes will be developed.” 

Reference

Bae D-J, Jun AE, Chang HS, Park JS, Park C-S. Epigenetic changes in asthma: role of DNA CpG methylation.Tuberc Respir Dis. 2020;83(1):1-13.