Epigenome alterations in food allergy: A systematic review of candidate gene and epigenome‐wide association studies

Abstract

Objective:The aim of this study was to systematically review the evidence across studies that assessed DNA methylome variations in association with food allergy (FA).Design: A systematic review of the literature and meta-analysis were carried out within several databases. However, the risk of bias in the included articles was not evaluated.Data sources: PubMed, Cochrane Database of Systematic Reviews, and Web of Science were used to search up to July 2022. Eligibility criteria:We included targeted and epigenome-wide association studies (EWASs) that assessed DNA methylome alterations in association with FA in adult or paediatric populations.Results: Among 366 publications, only 16 were retained, which were mainly focused on FA in children. Seven candidate gene-targeted studies found associations in Th1/ Th2 imbalance (IL4, IL5, IL10, INFG, IL2 and IL12B genes), regulatory T cell function (FOXP3 gene), Toll-like receptors pathway (TLR2, CD14 genes) and digestive barrier integrity (FLG gene). Nine EWAS assessed the association with peanut allergy (n = 3), cow's milk allergy (n = 2) or various food allergens (n = 4). They highlighted 11 differentially methylated loci in at least two studies (RPS6KA2, CAMTA1, CTBP2, RYR2, TRAPPC9, DOCK1, GALNTL4, HDAC4, UMODL1, ZAK and TNS3 genes). Among them, Food allergy (FA) is a current public health issue with an increasing incidence over time, suggesting potential epigenetic triggers. Nearly 8% of children have FA in the United States. 1 Food allergy can produce high alteration of the quality of life. In some cases, it may have a severe presentation with life-threatening complications, including fatal episodes of anaphylaxis. 2 There are more than 170 foods that have been reported to cause FA; among them, eight common foods (i.e., cow's milk, hen's egg, peanut, tree nuts, wheat, soy, fish and crustacean shellfish) are responsible for 90% of the reported FA CAMTA1 and RPS6KA2, and CTBP2 are involved in regulatory T cell function and Th2 cell differentiation, respectively. Gene-functional analysis revealed two enriched gene clusters involved in immune responses and protein phosphorylation. ChIP-X Enrichment Analysis 3 showed eight significant transcription factors (RXRA, ZBTB7A, ESR1, TCF3, MYOD1, CTCF, GATA3 and CBX2). Ingenuity Pathway Analysis identified canonical pathways involved, among other, in B cell development, pathogen-induced cytokine storm signalling pathway and dendritic cell maturation. Conclusion:This review highlights the involvement of epigenomic alterations of loci in Th1/Th2 and regulatory T cell differentiation in both candidate gene studies and EWAS. These alterations provide a better insight into the mechanistic aspects in FA pathogenesis and may guide the development of epigenome-based biomarkers for FA.

Epigenomic and epigenetic investigations of food allergy

“…For example, among the existing EWAS of food allergy, 11 genes have epigenetic loci reported in at least two studies, while many more were found in only one study. 26 between epigenetic changes and outcomes that may better inform on potential functional effects of epigenetics. 27 Third, testing of findings in independent cohorts additionally strengthens findings and the likelihood that results are relevant beyond the studied sample.…”

“…A limited number of population‐based epigenomic and epigenetic studies of food allergy have been conducted overall, with some overlap in food allergy‐associated epigenetic loci detected, but also many distinct findings from each study. For example, among the existing EWAS of food allergy, 11 genes have epigenetic loci reported in at least two studies, while many more were found in only one study 26 . Differences in study design, populations of the sampled participants, targeted cell type, and food allergy outcome definitions certainly contribute to the spectrum of findings reported.…”

Dietary strategies for early immune modulation in primary food allergy prevention

“…A recent systematic review explored the association between epigenetic changes in candidate genes associated with food allergy. 24 The review found evidence of epigenetic alteration in several gene loci involved in the maintenance of Th1/Th2 balance and Treg differentiation. These epigenetic changes may provide mechanistic insights into the pathogenesis of food allergies and may guide the development of novel diagnostic biomarkers.…”

“…Epigenetic histone modification and DNA methylation are heritable, reversible changes which affect the functionality of genetic information without changing the nucleotide sequence. A recent systematic review explored the association between epigenetic changes in candidate genes associated with food allergy 24. The review found evidence of epigenetic alteration in several gene loci involved in the maintenance of Th1/Th2 balance and Treg differentiation.…”

Optimising the management of peanut allergy by targeting immune plasticity

“…Food ingestion facilitates food allergen sampling by CD103+ dendritic cells from the luminal tract, enabling their presentation to the T-cell compartment, inducing forkhead box protein 3-positive T-regulatory cells and supporting a tolerogenic cytokine milieu. 2,3 A wide range of environmental factors may hinder natural tolerance acquisition, including genetic, [4][5][6] epigenetic, 7 microbial, [8][9][10][11] cutaneous [12][13][14] and gastro-intestinal mechanisms. 15 Disruption of tolerance may result in activation of Th2 cells and class-switching from IgA to allergen-specific IgE antibody manufacture both in the gut-associated lymphoid tissue and mucosal compartment and the development of food allergy.…”