Food allergy is a major clinical and public health concern worldwide. The risk factors are well defined, however, the mechanisms by which they affect immune development remain largely unknown, and unfortunately the effective treatment or prevention of food allergy is still being researched. Recent studies show that the genes that are critical for the development of food allergy are regulated through DNA methylation. Environmental factors can affect host DNA methylation status and subsequently predispose people to food allergy. DNA methylation is therefore an important mediator of gene-environment interactions in food allergy and key to understanding the mechanisms underlying the allergic development. Indeed, the modification and identification of the methylation levels of specific genetic loci have gained increasing attention for therapeutic and diagnostic application in combating food allergy. In this review, we summarize and discuss the recent developments of DNA methylation in food allergy, including the pathogenesis, therapy, and diagnosis. This review will also summarize and discuss the environmental factors that affect DNA methylation levels in food allergy.

Vassallo MF, Camargo CA Jr: Potential mechanisms for the hypothesized link between sunshine, vitamin D, and food allergy in children. J Allergy Clin Immunol 2010;126:217-222.
Gupta RS, Springston EE, Warrier MR, Smith B, Kumar R, Pongracic J, Holl JL: The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011;128:9-17.
Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V, Dubois AEJ, Halken S, Hoffmann-Sommergruber K, Poulsen LK, Roberts G, van Ree R, Vlieg-Boerstra BJ, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group: The epidemiology of food allergy in Europe: a systemic review and meta-analysis. Allergy 2014;69:62-75.
Dogruel D, Bingol G, Altintas DU, Yilmaz M, Guneser Kendirli S: Clinical features of food allergy during the 1st year of life: The ADAPAR Birth Cohort Study. Int Arch Allergy Immunol 2016;169:171-180.
Prescott SL, Pawankar R, Allen KJ, Campbell DE, Sinn JK, Fiocchi A, Ebisawa M, Sampson HA, Beyer K, Lee B-W: A global survey of changing patterns of food allergy burden in children. World Allergy Organ J 2013;6:21.
Prescott S, Allen KJ: Food allergy: riding the second wave of the allergy epidemic. Pediatr Allergy Immunol 2011;22:155-160.
Ho MH, Wong WH, Chang C: Clinical spectrum of food allergies: a comprehensive review. Clin Rev Allergy Immunol 2014;46:225-240.
Dogruel D, Bingol G, Yilmaz M, Altintas DU: The ADAPAR Birth Cohort Study: food allergy results at five years and new insights. Int Arch Allergy Immunol 2016;169:57-61.
Gernez Y, Nowak-Wegrzyn A: Immunotherapy for food allergy: are we there yet? J Allergy Clin Immunol Pract 2017;5:250-272.
Harb H, Renz H: Update on epigenetics in allergic disease. J Allergy Clin Immunol 2015;135:15-24.
Anderson OS, Sant KE, Dolinoy DC: Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem 2012;23:853-859.
North ML, Ellis AK: The role of epigenetics in the developmental origins of allergic disease. Ann Allergy Asthma Immunol 2011;106:355-361.
Kuriakose JS, Miller RL: Environmental epigenetics and allergic diseases: recent advances. Clin Exp Allergy 2010;40:1602-1610.
Szyf M, Bick J: DNA methylation: a mechanism for embedding early life experiences in the genome. Child Dev 2013;84:49-57.
Hinz D, Bauer M, Roder S, Olek S, Huehn J, Sack U, Borte M, Simon JC, Lehmann I, Herberth G; LINA Study Group: Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy 2012;67:380-389.
Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, Bailey N, Potts EN, Whitehead G, Brass DM, Schwartz DA: In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 2008;118:3462-3469.
Michel S, Busato F, Genuneit J, Pekkanen J, Dalphin JC, Riedler J, Mazaleyrat N, Weber J, Karvonen AM, Hirvonen MR, Braun-Fahrlander C, Lauener R, von Mutius E, Kabesch M, Tost J, group Ps, Hyvarinen A, Remes S, Tiittanen P, Roponen M, Dalphin M-L, Kaulek V, Buchele G, Depner M, Ege M, Schaub B, Pfefferle P, Renz H, Bitter S, Loss G, Frei R, Roduit C, Doeckes G: Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. Allergy 2013;68:355-364.
Yang IV, Pedersen BS, Liu A, O'Connor GT, Teach SJ, Kattan M, Misiak RT, Gruchalla R, Steinbach SF, Szefler SJ, Gill MA, Calatroni A, David G, Hennessy CE, Davidson EJ, Zhang W, Gergen P, Togias A, Busse WW, Schwartz DA: DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol 2015;136:69-80.
Kabesch M: Epigenetics in asthma and allergy. Curr Opin Allergy Clin Immunol 2014;14:62-68.
Razavi GSE, Allen T: Emerging role of interleukins in cancer treatment. Immunome Res 2015;2:1-17.
Song Y, Liu C, Hui Y, Srivastava K, Zhou Z, Chen J, Miller RL, Finkelman FD, Li X-M: Maternal allergy increases susceptibility to offspring allergy in association with TH2-biased epigenetic alterations in a mouse model of peanut allergy. J Allergy Clin Immunol 2014;134:1339-1345.
Berni Canani R, Paparo L, Nocerino R, Cosenza L, Pezzella V, Di Costanzo M, Capasso M, Del Monaco V, D'Argenio V, Greco L, Salvatore F: Differences in DNA methylation profile of Th1 and Th2 cytokine genes are associated with tolerance acquisition in children with IgE-mediated cow's milk allergy. Clin Epigenetics 2015;7:38.
Zbikowska-Gotz M, Palgan K, Gawronska-Ukleja E, Kuzminski A, Przybyszewski M, Socha E, Bartuzi Z: Expression of IL-17A concentration and effector functions of peripheral blood neutrophils in food allergy hypersensitivity patients. Int J Immunopathol Pharmacol 2016;29:90-98.
Sampath V, Tupa D, Graham MT, Chatila TA, Spergel JM, Nadeau KC: Deciphering the black box of food allergy mechanisms. Ann Allergy Asthma Immunol 2017;118:21-27.
Wang P, Sidney J, Kim Y, Sette A, Lund O, Nielsen M, Peters B: Peptide binding predictions for HLA DR, DP and DQ molecules. BMC Bioinformatics 2010;11:568.
Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S, Buus S, Lund O: Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLoS Computat Biol 2008;4:e1000107.
Hemler JA, Phillips EJ, Mallal SA, Kendall PL: The evolving story of human leukocyte antigen and the immunogenetics of peanut allergy. Ann Allergy Asthma Immunol 2015;115:471-476.
Bondinas GP, Moustakas AK, Papadopoulos GK: The spectrum of HLA-DQ and HLA-DR alleles, 2006: a listing correlating sequence and structure with function. Immunogenetics 2007;59:539-553.
Majumder P, Boss JM: DNA methylation dysregulates and silences the HLA-DQ locus by altering chromatin architecture. Genes Immun 2011;12:291-299.
Hong X, Hao K, Ladd-Acosta C, Hansen KD, Tsai H-J, Liu X, Xu X, Thornton TA, Caruso D, Keet CA, Sun Y, Wang G, Luo W, Kumar R, Fuleihan R, Singh AM, Kim JS, Story RE, Gupta RS, Gao P, Chen Z, Walker SO, Bartell TR, Beaty TH, Fallin MD, Schleimer R, Holt PG, Nadeau KC, Wood RA, Pongracic JA, Weeks DE, Wang X: Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children. Nat Commun 2015;6:6304.
Quake C, Nadeau KC: The role of epigenetic mediation and the future of food allergy research. Semin Cell Dev Biol 2015;43:125-130.
Syed A, Garcia MA, Lyu S-C, Bucayu R, Kohli A, Ishida S, Berglund JP, Tsai M, Maecker H, O'Riordan G, Galli SJ, Nadeau KC: Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol 2014;133:500-510.
Paparo L, Nocerino R, Cosenza L, Aitoro R, D'Argenio V, Del Monaco V, Di Scala C, Amoroso A, Di Costanzo M, Salvatore F, Berni Canani R: Epigenetic features of FoxP3 in children with cow's milk allergy. Clin Epigenetics 2016;8:86.
Ogrodowczyk A, Markiewicz L, Wroblewska B: Mutations in the filaggrin gene and food allergy. Prz Gastroenterol 2014;9:200-207.
Venkataraman D, Soto-Ramirez N, Kurukulaaratchy RJ, Holloway JW, Karmaus W, Ewart SL, Arshad SH, Erlewyn-Lajeunesse M: Filaggrin loss-of-function mutations are associated with food allergy in childhood and adolescence. J Allergy Clin Immunol 2014;134:876-882.
Tan HT, Ellis JA, Koplin JJ, Martino D, Dang TD, Suaini N, Saffery R, Allen KJ: Methylation of the filaggrin gene promoter does not affect gene expression and allergy. Pediatr Allergy Immunol 2014;25:608-610.
Petrus NCM, Henneman P, Venema A, Mul A, van Sinderen F, Haagmans M, Mook O, Hennekam RC, Sprikkelman AB, Mannens M: Cow's milk allergy in Dutch children: an epigenetic pilot survey. Clin Transl Allergy 2016;6:16.
Hong X, Ladd-Acosta C, Hao K, Sherwood B, Ji H, Keet CA, Kumar R, Caruso D, Liu X, Wang G, Chen Z, Ji Y, Mao G, Walker SO, Bartell TR, Ji Z, Sun Y, Tsai H-J, Pongracic JA, Weeks DE, Wang X: Epigenome-wide association study links site-specific DNA methylation changes with cow's milk allergy. J Allergy Clin Immunol 2016;138:908-911.e909.
Akbari O, Umetsu DT: Role of regulatory dendritic cells in allergy and asthma. Curr Allergy Asthma Rep 2005;5:56-61.
Suarez-Alvarez B, Baragano Raneros A, Ortega F, Lopez-Larrea C: Epigenetic modulation of the immune function: a potential target for tolerance. Epigenetics 2013;8:694-702.
Gorelik M, Frischmeyer-Guerrerio PA: Innate and adaptive dendritic cell responses to immunotherapy. Curr Opin Allergy Clin Immunol 2015;15:575-580.
Berni Canani R, Nocerino R, Terrin G, Frediani T, Lucarelli S, Cosenza L, Passariello A, Leone L, Granata V, Di Costanzo M, Pezzella V, Troncone R: Formula selection for management of children with cow's milk allergy influences the rate of acquisition of tolerance: a prospective multicenter study. J Pediatr 2013;163:771-777.
Mondoulet L, Dioszeghy V, Puteaux E, Ligouis M, Dhelft V, Plaquet C, Dupont C, Benhamou P-H: Specific epicutaneous immunotherapy prevents sensitization to new allergens in a murine model. J Allergy Clin Immunol 2015;135:1546-1557.
Tost J, Mondoulet L, Puteaux E, Busato F, Ligouis M, Dhelft V, Plaquet C, Dupont C, Benhamou P: Epicutaneous but not oral immunotherapy leads to sustainable GATA-3 hypermethylation and Foxp3 hypomethylation in peanut sensitized mice. J Allergy Clin Immunol 2016;137.
He W, Yang C, Xia L, Zhao M-Z, Ge R-T, Huang H, Ji Q, Yang P-C, Liu Z: CD4+ T cells from food allergy model are resistant to TCR-dependent apoptotic induction. Cytokine 2014;68:32-39.
Yang G, Geng X-R, Liu Z-Q, Liu J-Q, Liu X-Y, Xu L-Z, Zhang H-P, Sun Y-X, Liu Z-G, Yang P-C: Thrombospondin-1 (TSP1)-producing B cells restore antigen (Ag)-specific immune tolerance in an allergic environment. J Biol Chem 2015;290:12858-12867.
Tan THT, Ellis JA, Saffery R, Allen KJ: The role of genetics and environment in the rise of childhood food allergy. Clin Exp Allergy 2012;42:20-29.
Li J, Maggadottir SM, Hakonarson H: Are genetic tests informative in predicting food allergy? Curr Opin Allergy Clin Immunol 2016;16:257-264.
Martino D, Dang T, Sexton-Oates A, Prescott S, Tang M, Dharmage S, Gurrin L, Koplin J, Ponsonby A, Allen KJ, Saffery R: Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants. J Allergy Clin Immunol 2015;135:1319-1328.e12.
Martino D, Dang T, Sexton-Oates A, Prescott S, Tang MLK, Dharmage S, Gurrin L, Koplin J, Ponsonby A, Allen KJ, Saffery R: Using methylation signatures to distinguish food allergy from tolerance. Pathology 2016;48:S47-S48.
Calvani M, Berti I, Fiocchi A, Galli E, Giorgio V, Martelli A, Miceli Sopo S, Panetta V: Oral food challenge: safety, adherence to guidelines and predictive value of skin prick testing. Pediatr Allergy Immunol 2012;23:755-761.
Prescott S, Saffery R: The role of epigenetic dysregulation in the epidemic of allergic disease. Clin Epigenetics 2011;2:223-232.
Song Y, Sampson H, Li X: Maternal low dose peanut and cholera toxin subunit B induces oral tolerance associated with an increased number of T regulatory cells. J Allergy Clin Immunol 2012;129.
Yang K, Wu J, Zhong Y, Cai W: Vitamin D deficiency in early life leads to food allergy by down-regulating Treg cells in BALB/c mice. FASEB J 2015;29(suppl):758.7.
Weisse K, Winkler S, Hirche F, Herberth G, Hinz D, Bauer M, Roder S, Rolle-Kampczyk U, von Bergen M, Olek S, Sack U, Richter T, Diez U, Borte M, Stangl GI, Lehmann I: Maternal and newborn vitamin D status and its impact on food allergy development in the German LINA cohort study. Allergy 2013;68:220-228.
Tsabouri S, Priftis KN, Chaliasos N, Siamopoulou A: Modulation of gut microbiota downregulates the development of food allergy in infancy. Allergol Immunopathol 2014;42:69-77.
Rodriguez B, Prioult G, Bibiloni R, Nicolis I, Mercenier A, Butel M-J, Waligora-Dupriet A-J: Germ-free status and altered caecal subdominant microbiota are associated with a high susceptibility to cow's milk allergy in mice. FEMS Microbiol Ecol 2011;76:133-144.
Rodriguez B, Prioult G, Hacini-Rachinel F, Moine D, Bruttin A, Ngom-Bru C, Labellie C, Nicolis I, Berger B, Mercenier A, Butel M-J, Waligora-Dupriet A-J: Infant gut microbiota is protective against cow's milk allergy in mice despite immature ileal T-cell response. FEMS Microbiol Ecol 2012;79:192-202.
West CE, Jenmalm MC, Prescott SL: The gut microbiota and its role in the development of allergic disease: a wider perspective. Clin Exp Allergy 2015;45:43-53.
Diesner SC, Bergmayr C, Pfitzner B, Assmann V, Krishnamurthy D, Starkl P, Endesfelder D, Rothballer M, Welzl G, Rattei T, Eiwegger T, Szepfalusi Z, Fehrenbach H, Jensen-Jarolim E, Hartmann A, Pali-Scholl I, Untersmayr E: A distinct microbiota composition is associated with protection from food allergy in an oral mouse immunization model. Clin Immunol 2016;173:10-18.
Hesson LB: Gut microbiota and obesity-related gastrointestinal cancer: a focus on epigenetics. Translat Gastrointest Cancer 2013;2:204-210.
Tuokkola J, Luukkainen P, Kaila M, Takkinen H-M, Niinisto S, Veijola R, Virta LJ, Knip M, Simell O, Ilonen J, Virtanen SM: Maternal dietary folate, folic acid and vitamin D intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring. Br J Nutr 2016;116:710-718.
Paul B, Barnes S, Demark-Wahnefried W, Morrow C, Salvador C, Skibola C, Tollefsbol TO: Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clin Epigenet 2015;7:112.
Berni Canani R, Sangwan N, Stefka AT, Nocerino R, Paparo L, Aitoro R, Calignano A, Khan AA, Gilbert JA, Nagler CR: Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants. ISME J 2016;10:742-750.
Panjari M, Koplin JJ, Dharmage SC, Peters RL, Gurrin LC, Sawyer SM, McWilliam V, Eckert JK, Vicendese D, Erbas B, Matheson MC, Tang MLK, Douglass J, Ponsonby AL, Dwyer T, Goldfeld S, Allen KJ: Nut allergy prevalence and differences between Asian-born children and Australian-born children of Asian descent: a state-wide survey of children at primary school entry in Victoria, Australia. Clin Exp Allergy 2016;46:602-609.
Zhang G, Wang K, Schultz E, Khoo S-K, Zhang X, Annamalay A, Laing IA, Hales BJ, Goldblatt J, Le Souef PN: Western environment/lifestyle is associated with increased genome methylation and decreased gene expression in Chinese immigrants living in Australia. Environ Mol Mutagen 2016;57:65-73.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.