Epigenome-wide association studies of allergic disease and the environment

Abstract

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. 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. Allergic diseases are a growing health concern worldwide, and recent studies have implicated epigenetic mechanisms with allergy. Epigenetic modifications are changes in gene expression not related to variations in the genetic code that can act as an interface between environmental exposures, lifestyle, and allergic diseases.1Harb H. Renz H. Update on epigenetics in allergic disease.J Allergy Clin Immunol. 2015; 135: 15-24Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 2Potaczek D.P. Harb H. Michel S. Alhamwe B.A. Renz H. Tost J. Epigenetics and allergy: from basic mechanisms to clinical applications.Epigenomics. 2017; 9: 539-571Crossref PubMed Scopus (191) Google Scholar, 3Li Y. Rui X. Ma B. Jiang F. Chen J. Early-life environmental factors, IFN-γ methylation patterns, and childhood allergic rhinitis.Int Arch Allergy Immunol. 2019; 178: 323-332Crossref PubMed Scopus (12) Google Scholar Asthma, allergic rhinitis, atopic dermatitis, and food allergy affect up to 20% of the world’s population, and these prevalent diseases can significantly affect quality of life and cause substantial direct and indirect costs to society.4Dierick B.J.H. van der Molen T. Flokstra-de Blok B.M.J. Muraro A. Postma M.J. Kocks J.W.H. et al.Burden and socioeconomics of asthma, allergic rhinitis, atopic dermatitis and food allergy.Expert Rev Pharmacoecon Outcomes Res. 2020; 20: 437-453Crossref PubMed Scopus (122) Google Scholar Lifestyle factors, such as dietary habits, delayed introduction of food allergens, and hygienic practices, as well as environmental factors, such as exposure to cigarette smoke, air pollution, microbes, and allergens (some of which can be aggravated by climate change), may all contribute to disease onset and severity.5Melén E. Koppelman G.H. Vicedo-Cabrera A.M. Andersen Z.J. Bunyavanich S. Allergies to food and airborne allergens in children and adolescents: role of epigenetics in a changing environment.Lancet Child Adolesc Health. 2022; 6: 810-819Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Epigenetics research on the mechanisms and biomarkers of allergic disease may help elucidate how environmental exposures in the prenatal period and early life promote allergy throughout the life course and across generations. Many scientists have proposed that the epigenome is key to understanding allergic disease, given both the role of the environment in allergic disease and robust evidence on the influence of some environmental factors on the human epigenome.6Qi Koppelman G.H. The role of epigenetics in the of childhood Rev Clin Immunol. 2019; PubMed Scopus Google Scholar, A. B.A. et nasal as a biomarker of asthma and in 2019; PubMed Scopus Google Scholar, The environment, and Allergy Clin Immunol. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar the epigenome-wide association studies (EWASs) have been to the between environmental factors and allergic diseases and DNA methylation of and E. Koppelman G.H. Vicedo-Cabrera A.M. Andersen Z.J. Bunyavanich S. Allergies to food and airborne allergens in children and adolescents: role of epigenetics in a changing environment.Lancet Child Adolesc Health. 2022; 6: 810-819Abstract Full Text Full Text PDF PubMed Scopus (17) Google Koppelman G.H. E. on the epigenetics of Allergy Clin Immunol. PubMed Scopus Google Scholar In this narrative review, we and discuss recent findings within the of the with the to the these the of environmental exposures to in epigenetic related to allergy and We have this on EWASs of DNA as this has allergic diseases and many environmental factors to allergy in a across human We on and discuss findings from and recent EWASs on this we an of epigenetic challenges, and findings from epigenetic and discuss clinical The of EWASs is to examine epigenetic across the to in DNA methylation at a given in to an exposure or of A. J. H. et association and PubMed Scopus Google Scholar DNA is from a of of tissues and which results in a from to DNA is to on such as the or to across the are by using and the of DNA at a certain is a or exposure of with A. J. H. et association and PubMed Scopus Google Scholar In to the of and in the have been to S. 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