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Genetics, epigenetics, and allergic disease: A gun loaded by genetics and a trigger pulled by epigenetics.

T allergic diseases addressed in this issue comprise a group of disorders mediated by chronic allergic inflammation and frequently activated by immunoglobulin E. The prevalence and severity of many of these allergic disorders have increased dramatically over the past few decades, creating a mystery as to why. Although genetics plays an important role in the development of atopy, genetics alone cannot fully explain this rapid growth. In this issue, a review article by Bellanti may help us understand the important role that epigenetics plays in the development and management of allergic disease. An evidence-based proposal is presented that posits that DNA methylation plays a major role in epigenetic mechanisms involved in both the development of allergic disease as well as in the response to immunotherapy. The article reviewed the application of DNA methylation and regulatory T cell induction not only to allergic disorders but also to cancer and autoimmune diseases. Bellanti illustrated the relationship between genetics and epigenetics with the comparative analogy, “genetics loads the gun and epigenetics pulls the trigger.” It is also apparent that epigenetics holds the key to unraveling the complex associations between disease phenotypes and endotypes by identifying safer and effective therapies, and by improving diagnosis and treatment of allergic diseases. Among the chronic, inflammatory, allergic diseases, none illustrate the genetics-epigenetics paradigm better than atopic dermatitis, and, as such, it has been featured as a recurring topic in recent issues of the Proceedings. Genetic predisposition, epidermal barrier disruption, and dysregulation of the immune system are some of the critical pathophysiologic components that lead to this condition. In this issue, Kim et al. provided an updated review of the pathophysiology of atopic dermatitis, with a particular focus on the role of epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis. The role of epigenetics in the development of atopic dermatitis is comprehensively reviewed by the authors, who cite increasing evidence that demonstrates that environmental exposures of patients with atopic dermatitis induce epigenetic changes through DNA modification and micro-RNA–mediated posttranscriptional regulation. Understanding this complex pathophysiology allows for development of a contemporary precision medicine approach to the prevention and the treatment of atopic dermatitis. In this way, the insights provided by Kim et al. directly relate to newer therapeutic strategies that are becoming available for the management of this condition. In transitioning from the most common, chronic, inflammatory, cutaneous disease of childhood to one more rare, Ertugrul et al. presented the results of their investigation of 32 children with cutaneous mastocytosis. These authors directed their efforts to discover prognostic factors for achieving remission and to determine the concomitant diagnostic value of DNA analysis of peripheral blood for the c-Kit mutation. Although the authors identified a number of useful prognostic factors, such as a triggering effect of tobacco exposure and of clarithromycin and vitamin D usage, they found that testing peripheral blood for the c-Kit mutation provided no diagnostic contribution in their cohort of pediatric patients with cutaneous mastocytosis. In moving on to another rare cutaneous disease, hereditary angioedema (HAE) is an autosomal dominant, genetic disorder associated with C1-inhibitor deficiency, which has been a recurrent topic in the Proceedings due to the recent development of a multitude of novel treatment options. In this issue, ArceAyala et al. reported on the clinical profile and quality of life displayed by Puerto Rican patients with HAE. Compared with U.S. population norms for quality-oflife measures, in Puerto Rico, patients with HAE manifested significantly lower scores, both in the physical and mental components. Arce-Ayala et al. have expanded the understanding of the burden of illness attributable to HAE by having demonstrated a substantial and noteworthy decrease in quality of life in patients with HAE and an increase risk for depression associated with the disorder. The burden of illness attributable to disease in general involves the direct cost attributable to treatment, in addition to measures of human suffering. A major factor that contributes to the cost of care is hospitalization, with asthma being among the costliest of the allergic diseases. Research that can lead to reduced Copyright © 2019, OceanSide Publications, Inc., U.S.A.