Skip to main content
Top
Published in: Clinical and Translational Allergy 1/2016

Open Access 01-12-2016 | Research

Cow’s milk allergy in Dutch children: an epigenetic pilot survey

Authors: Nicole C. M. Petrus, Peter Henneman, Andrea Venema, Adri Mul, Femke van Sinderen, Martin Haagmans, Olaf Mook, Raoul C. Hennekam, Aline B. Sprikkelman, Marcel Mannens

Published in: Clinical and Translational Allergy | Issue 1/2016

Login to get access

Abstract

Background

Cow’s milk allergy (CMA) is a common disease in infancy. Early environmental factors are likely to contribute to CMA. It is known that epigenetic gene regulation can be altered by environmental factors. We have set up a proof of concept study, aiming to detect epigenetic associations specific with CMA.

Methods

We studied children from the Dutch EuroPrevall birth cohort study (N = 20 CMA, N = 23 controls, N = 10 tolerant boys), age and gender matched. CMA was challenge proven. Bisulfite converted DNA (blood) was analyzed using the 450K infinium DNA-methylation array. Four groups (combined, girls, boys and tolerant boys) were analysed between CMA and controls. Statistical analysis and pathway-analysis were performed in “R” using IMA, Minfi and the global-test package. Differentially methylated regions in DHX58, ZNF281, EIF42A and HTRA2 genes were validated by quantitative amplicon sequencing (ROCHE 454®).

Results

General hypermethylation was found in the CMA group compared to control children, while this effect was absent in the tolerant group. Methylation differences were, among others, found in regions of DHX58, ZNF281, EIF42A and HTRA2 genes. Several of these genes are known to be involved in immunological pathways and associated with other allergies.

Conclusion

We show that epigenetic associations are involved in CMA. Although, the statistical power of our study is limited and our sample was based on whole blood, we were still able to detect feasible loci and pathways. Therefore our findings might contribute to future diagnostic or therapeutic interventions for specific CMA. Further studies have to confirm the findings of our study.
Appendix
Available only for authorised users
Literature
1.
go back to reference Chafen JJ, Newberry SJ, Riedl MA, Bravata DM, Maglione M, Suttorp MJ, et al. Diagnosing and managing common food allergies: a systematic review. JAMA. 2010;303(18):1848–56.CrossRefPubMed Chafen JJ, Newberry SJ, Riedl MA, Bravata DM, Maglione M, Suttorp MJ, et al. Diagnosing and managing common food allergies: a systematic review. JAMA. 2010;303(18):1848–56.CrossRefPubMed
2.
go back to reference Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2007;120(3):638–46.CrossRefPubMed Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. 2007;120(3):638–46.CrossRefPubMed
3.
go back to reference Schoemaker AA, Sprikkelman AB, Grimshaw KE, Roberts G, Grabenhenrich L, Rosenfeld L, et al. Incidence and natural history of challenge-proven cow’s milk allergy in European children–EuroPrevall birth cohort. Allergy. 2015;70(8):963–72.CrossRefPubMed Schoemaker AA, Sprikkelman AB, Grimshaw KE, Roberts G, Grabenhenrich L, Rosenfeld L, et al. Incidence and natural history of challenge-proven cow’s milk allergy in European children–EuroPrevall birth cohort. Allergy. 2015;70(8):963–72.CrossRefPubMed
4.
go back to reference Benhamou AH, Schappi Tempia MG, Belli DC, Eigenmann PA. An overview of cow’s milk allergy in children. Swiss Med Wkly. 2009;139(21–22):300–7.PubMed Benhamou AH, Schappi Tempia MG, Belli DC, Eigenmann PA. An overview of cow’s milk allergy in children. Swiss Med Wkly. 2009;139(21–22):300–7.PubMed
5.
go back to reference Tsai HJ, Kumar R, Pongracic J, Liu X, Story R, Yu Y, et al. Familial aggregation of food allergy and sensitization to food allergens: a family-based study. Clin Exp Allergy. 2009;39(1):101–9.CrossRefPubMedPubMedCentral Tsai HJ, Kumar R, Pongracic J, Liu X, Story R, Yu Y, et al. Familial aggregation of food allergy and sensitization to food allergens: a family-based study. Clin Exp Allergy. 2009;39(1):101–9.CrossRefPubMedPubMedCentral
6.
go back to reference Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy. 2008;63(11):1418–27.CrossRefPubMed Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy. 2008;63(11):1418–27.CrossRefPubMed
7.
go back to reference Matsumoto K, Saito H. epicutaneous immunity and onset of allergic diseases-per-”eczema” tous sensitization drives the allergy march. Allergol Int. 2013;62(3):291–6.CrossRefPubMed Matsumoto K, Saito H. epicutaneous immunity and onset of allergic diseases-per-”eczema” tous sensitization drives the allergy march. Allergol Int. 2013;62(3):291–6.CrossRefPubMed
8.
go back to reference Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic diseases. Clin Exp Allergy. 2005;35(12):1511–20.CrossRefPubMed Noverr MC, Huffnagle GB. The ‘microflora hypothesis’ of allergic diseases. Clin Exp Allergy. 2005;35(12):1511–20.CrossRefPubMed
9.
go back to reference Host A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow’s milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol. 2002;13(Suppl 15):23–8.CrossRefPubMed Host A, Halken S, Jacobsen HP, Christensen AE, Herskind AM, Plesner K. Clinical course of cow’s milk protein allergy/intolerance and atopic diseases in childhood. Pediatr Allergy Immunol. 2002;13(Suppl 15):23–8.CrossRefPubMed
10.
go back to reference Saarinen KM, Pelkonen AS, Makela MJ, Savilahti E. Clinical course and prognosis of cow’s milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol. 2005;116(4):869–75.CrossRefPubMed Saarinen KM, Pelkonen AS, Makela MJ, Savilahti E. Clinical course and prognosis of cow’s milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol. 2005;116(4):869–75.CrossRefPubMed
11.
go back to reference Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and immunological type of hypersensitivity reaction. Allergy. 1990;45(8):587–96.CrossRefPubMed Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and immunological type of hypersensitivity reaction. Allergy. 1990;45(8):587–96.CrossRefPubMed
12.
go back to reference Longo G, Berti I, Burks AW, Krauss B, Barbi E. IgE-mediated food allergy in children. Lancet. 2013;382(9905):1656–64.CrossRefPubMed Longo G, Berti I, Burks AW, Krauss B, Barbi E. IgE-mediated food allergy in children. Lancet. 2013;382(9905):1656–64.CrossRefPubMed
13.
go back to reference Morita H, Nomura I, Matsuda A, Saito H, Matsumoto K. Gastrointestinal food allergy in infants. Allergol Int. 2013;62(3):297–307.CrossRefPubMed Morita H, Nomura I, Matsuda A, Saito H, Matsumoto K. Gastrointestinal food allergy in infants. Allergol Int. 2013;62(3):297–307.CrossRefPubMed
14.
go back to reference Tan TH, Ellis JA, Saffery R, Allen KJ. The role of genetics and environment in the rise of childhood food allergy. Clin Exp Allergy. 2012;42(1):20–9.CrossRefPubMed Tan TH, Ellis JA, Saffery R, Allen KJ. The role of genetics and environment in the rise of childhood food allergy. Clin Exp Allergy. 2012;42(1):20–9.CrossRefPubMed
17.
go back to reference Anacker C, O’Donnell KJ, Meaney MJ. Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function. Dialogues Clin Neurosci. 2014;16(3):321–33.PubMedPubMedCentral Anacker C, O’Donnell KJ, Meaney MJ. Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function. Dialogues Clin Neurosci. 2014;16(3):321–33.PubMedPubMedCentral
18.
go back to reference Andersson NW, Hansen MV, Larsen AD, Hougaard KS, Kolstad HA, Schlunssen V. Prenatal maternal stress and atopic diseases in the child: a systematic review of observational human studies. Allergy. 2016;71(1):15–26.CrossRefPubMed Andersson NW, Hansen MV, Larsen AD, Hougaard KS, Kolstad HA, Schlunssen V. Prenatal maternal stress and atopic diseases in the child: a systematic review of observational human studies. Allergy. 2016;71(1):15–26.CrossRefPubMed
19.
20.
go back to reference Prescott SL, Pawankar R, Allen KJ, Campbell DE, Sinn JK, Fiocchi A, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J. 2013;6(1):21.CrossRefPubMedPubMedCentral Prescott SL, Pawankar R, Allen KJ, Campbell DE, Sinn JK, Fiocchi A, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J. 2013;6(1):21.CrossRefPubMedPubMedCentral
21.
go back to reference Naumova AK, Al TA, Morin A, Vaillancourt VT, Madore AM, Berlivet S, et al. Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma. Hum Genet. 2013;132(7):811–22.CrossRefPubMed Naumova AK, Al TA, Morin A, Vaillancourt VT, Madore AM, Berlivet S, et al. Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma. Hum Genet. 2013;132(7):811–22.CrossRefPubMed
22.
go back to reference Vink NM, Postma DS, Schouten JP, Rosmalen JG, Boezen HM. Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents’ Individual Lives Survey (TRAILS) study. J Allergy Clin Immunol. 2010;126(3):498–504.CrossRefPubMed Vink NM, Postma DS, Schouten JP, Rosmalen JG, Boezen HM. Gender differences in asthma development and remission during transition through puberty: the TRacking Adolescents’ Individual Lives Survey (TRAILS) study. J Allergy Clin Immunol. 2010;126(3):498–504.CrossRefPubMed
23.
go back to reference DunnGalvin A, Hourihane JO, Frewer L, Knibb RC, Oude Elberink JN, Klinge I. Incorporating a gender dimension in food allergy research: a review. Allergy. 2006;61(11):1336–43.CrossRefPubMed DunnGalvin A, Hourihane JO, Frewer L, Knibb RC, Oude Elberink JN, Klinge I. Incorporating a gender dimension in food allergy research: a review. Allergy. 2006;61(11):1336–43.CrossRefPubMed
24.
go back to reference Kelly C, Gangur V. Sex disparity in food allergy: evidence from the PubMed database. J Allergy (Cairo). 2009;2009:159845. Kelly C, Gangur V. Sex disparity in food allergy: evidence from the PubMed database. J Allergy (Cairo). 2009;2009:159845.
25.
go back to reference Keil T, McBride D, Grimshaw K, Niggemann B, Xepapadaki P, Zannikos K, et al. The multinational birth cohort of EuroPrevall: background, aims and methods. Allergy. 2010;65(4):482–90.CrossRefPubMed Keil T, McBride D, Grimshaw K, Niggemann B, Xepapadaki P, Zannikos K, et al. The multinational birth cohort of EuroPrevall: background, aims and methods. Allergy. 2010;65(4):482–90.CrossRefPubMed
26.
go back to reference McBride D, Keil T, Grabenhenrich L, Dubakiene R, Drasutiene G, Fiocchi A, et al. The EuroPrevall birth cohort study on food allergy: baseline characteristics of 12,000 newborns and their families from nine European countries. Pediatr Allergy Immunol. 2012;23(3):230–9.CrossRefPubMed McBride D, Keil T, Grabenhenrich L, Dubakiene R, Drasutiene G, Fiocchi A, et al. The EuroPrevall birth cohort study on food allergy: baseline characteristics of 12,000 newborns and their families from nine European countries. Pediatr Allergy Immunol. 2012;23(3):230–9.CrossRefPubMed
27.
go back to reference Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report. J Allergy Clin Immunol. 2010;126(6):1105–18.CrossRefPubMedPubMedCentral Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report. J Allergy Clin Immunol. 2010;126(6):1105–18.CrossRefPubMedPubMedCentral
28.
go back to reference Petrus NC, Schoemaker AF, van Hoek MW, Jansen L, Jansen-van der Weide MC, van Aalderen WM, Sprikkelman AB. Remaining symptoms in half the children treated for milk allergy. Eur J Pediatr. 2015;174(6):759–65.CrossRefPubMed Petrus NC, Schoemaker AF, van Hoek MW, Jansen L, Jansen-van der Weide MC, van Aalderen WM, Sprikkelman AB. Remaining symptoms in half the children treated for milk allergy. Eur J Pediatr. 2015;174(6):759–65.CrossRefPubMed
29.
go back to reference Henneman P, Petrus NC, Venema A, van SF, van der Lip K, Hennekam RC, et al. Genetic susceptibility for cow’s milk allergy in Dutch children: the start of the allergic march? Clin Transl Allergy. 2015;6:7.CrossRefPubMedPubMedCentral Henneman P, Petrus NC, Venema A, van SF, van der Lip K, Hennekam RC, et al. Genetic susceptibility for cow’s milk allergy in Dutch children: the start of the allergic march? Clin Transl Allergy. 2015;6:7.CrossRefPubMedPubMedCentral
30.
go back to reference Houseman EA, Kelsey KT, Wiencke JK, Marsit CJ. Cell-composition effects in the analysis of DNA methylation array data: a mathematical perspective. BMC Bioinform. 2015;16:95.CrossRef Houseman EA, Kelsey KT, Wiencke JK, Marsit CJ. Cell-composition effects in the analysis of DNA methylation array data: a mathematical perspective. BMC Bioinform. 2015;16:95.CrossRef
31.
go back to reference Chen YA, Lemire M, Choufani S, Butcher DT, Grafodatskaya D, Zanke BW, et al. Discovery of cross-reactive probes and polymorphic CpGs in the illumina infinium humanmethylation450 microarray. Epigenetics. 2013;8(2):203–9.CrossRefPubMedPubMedCentral Chen YA, Lemire M, Choufani S, Butcher DT, Grafodatskaya D, Zanke BW, et al. Discovery of cross-reactive probes and polymorphic CpGs in the illumina infinium humanmethylation450 microarray. Epigenetics. 2013;8(2):203–9.CrossRefPubMedPubMedCentral
32.
go back to reference Goeman JJ, van de Geer SA, de KF, van Houwelingen HC. A global test for groups of genes: testing association with a clinical outcome. Bioinformatics. 2004;20(1):93–9.CrossRefPubMed Goeman JJ, van de Geer SA, de KF, van Houwelingen HC. A global test for groups of genes: testing association with a clinical outcome. Bioinformatics. 2004;20(1):93–9.CrossRefPubMed
34.
go back to reference Bonnelykke K, Sparks R, Waage J, Milner JD. Genetics of allergy and allergic sensitization: common variants, rare mutations. Curr Opin Immunol. 2015;36:115–26.CrossRefPubMed Bonnelykke K, Sparks R, Waage J, Milner JD. Genetics of allergy and allergic sensitization: common variants, rare mutations. Curr Opin Immunol. 2015;36:115–26.CrossRefPubMed
35.
go back to reference Berni CR, Paparo L, Nocerino R, Cosenza L, Pezzella V, Di CM, et al. 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(1):38.CrossRef Berni CR, Paparo L, Nocerino R, Cosenza L, Pezzella V, Di CM, et al. 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(1):38.CrossRef
36.
go back to reference Martino D, Joo JE, Sexton-Oates A, Dang T, Allen K, Saffery R, Prescott S. Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy. Epigenetics. 2014;9(7):998–1006.CrossRefPubMedPubMedCentral Martino D, Joo JE, Sexton-Oates A, Dang T, Allen K, Saffery R, Prescott S. Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy. Epigenetics. 2014;9(7):998–1006.CrossRefPubMedPubMedCentral
38.
go back to reference Walker-Smith J. Cow’s milk allergy: a new understanding from immunology. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):81–3.CrossRefPubMed Walker-Smith J. Cow’s milk allergy: a new understanding from immunology. Ann Allergy Asthma Immunol. 2003;90(6 Suppl 3):81–3.CrossRefPubMed
40.
go back to reference Melnik BC, John SM, Schmitz G. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth. Nutr J. 2013;12:103.CrossRefPubMedPubMedCentral Melnik BC, John SM, Schmitz G. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth. Nutr J. 2013;12:103.CrossRefPubMedPubMedCentral
41.
go back to reference Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013;13(10):722–37.CrossRefPubMed Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol. 2013;13(10):722–37.CrossRefPubMed
42.
go back to reference Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010;105(2):99–106.CrossRefPubMed Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010;105(2):99–106.CrossRefPubMed
44.
go back to reference Illi S, Voon ME, Lau S, Nickel R, Gruber C, Niggemann B, Wahn U. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004;113(5):925–31.CrossRefPubMed Illi S, Voon ME, Lau S, Nickel R, Gruber C, Niggemann B, Wahn U. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004;113(5):925–31.CrossRefPubMed
45.
go back to reference Nissen SP, Kjaer HF, Host A, Nielsen J, Halken S. The natural course of sensitization and allergic diseases from childhood to adulthood. Pediatr Allergy Immunol. 2013;24(6):549–55.CrossRefPubMed Nissen SP, Kjaer HF, Host A, Nielsen J, Halken S. The natural course of sensitization and allergic diseases from childhood to adulthood. Pediatr Allergy Immunol. 2013;24(6):549–55.CrossRefPubMed
47.
go back to reference Amanna IJ, Slifka MK. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol Rev. 2010;236:125–38.CrossRefPubMed Amanna IJ, Slifka MK. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol Rev. 2010;236:125–38.CrossRefPubMed
48.
go back to reference Amarasekera M, Prescott SL, Palmer DJ. Nutrition in early life, immune-programming and allergies: the role of epigenetics. Asian Pac J Allergy Immunol. 2013;31(3):175–82.PubMed Amarasekera M, Prescott SL, Palmer DJ. Nutrition in early life, immune-programming and allergies: the role of epigenetics. Asian Pac J Allergy Immunol. 2013;31(3):175–82.PubMed
49.
go back to reference De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, Pena-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2010;(10):CD007950. doi:10.1002/14651858.CD007950.pub2 De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, Pena-Rosas JP. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev 2010;(10):CD007950. doi:10.​1002/​14651858.​CD007950.​pub2
50.
go back to reference Harb H, Renz H. Update on epigenetics in allergic disease. J Allergy Clin Immunol. 2015;135(1):15–24.CrossRefPubMed Harb H, Renz H. Update on epigenetics in allergic disease. J Allergy Clin Immunol. 2015;135(1):15–24.CrossRefPubMed
51.
go back to reference Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet. 2002;10(11):682–8.CrossRefPubMed Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet. 2002;10(11):682–8.CrossRefPubMed
52.
go back to reference Tooley KL, El-Merhibi A, Cummins AG, Grose RH, Lymn KA, DeNichilo M, Penttila IA. Maternal milk, but not formula, regulates the immune response to beta-lactoglobulin in allergy-prone rat pups. J Nutr. 2009;139(11):2145–51.CrossRefPubMed Tooley KL, El-Merhibi A, Cummins AG, Grose RH, Lymn KA, DeNichilo M, Penttila IA. Maternal milk, but not formula, regulates the immune response to beta-lactoglobulin in allergy-prone rat pups. J Nutr. 2009;139(11):2145–51.CrossRefPubMed
Metadata
Title
Cow’s milk allergy in Dutch children: an epigenetic pilot survey
Authors
Nicole C. M. Petrus
Peter Henneman
Andrea Venema
Adri Mul
Femke van Sinderen
Martin Haagmans
Olaf Mook
Raoul C. Hennekam
Aline B. Sprikkelman
Marcel Mannens
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Clinical and Translational Allergy / Issue 1/2016
Electronic ISSN: 2045-7022
DOI
https://doi.org/10.1186/s13601-016-0105-z

Other articles of this Issue 1/2016

Clinical and Translational Allergy 1/2016 Go to the issue

Reviewer acknowledgement

Reviewer acknowledgement 2015