Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants

doi:10.1016/j.jaci.2014.12.1933

Journal of Allergy and Clinical Immunology

Volume 135, Issue 5, May 2015, Pages 1319-1328.e12

https://doi.org/10.1016/j.jaci.2014.12.1933 Get rights and content

Background

The diagnosis of food allergy (FA) can be challenging because approximately half of food-sensitized patients are asymptomatic. Current diagnostic tests are excellent makers of sensitization but poor predictors of clinical reactivity. Thus oral food challenges (OFCs) are required to determine a patient's risk of reactivity.

Objective

We sought to discover genomic biomarkers of clinical FA with utility for predicting food challenge outcomes.

Methods

Genome-wide DNA methylation (DNAm) profiling was performed on blood mononuclear cells from volunteers who had undergone objective OFCs, concurrent skin prick tests, and specific IgE tests. Fifty-eight food-sensitized patients (aged 11-15 months) were assessed, half of whom were clinically reactive. Thirteen nonallergic control subjects were also assessed. Reproducibility was assessed in an additional 48 samples by using methylation data from an independent population of patients with clinical FA.

Results

Using a supervised learning approach, we discovered a DNAm signature of 96 CpG sites that predict clinical outcomes. Diagnostic scores were derived from these 96 methylation sites, and cutoffs were determined in a sensitivity analysis. Methylation biomarkers outperformed allergen-specific IgE and skin prick tests for predicting OFC outcomes. FA status was correctly predicted in the replication cohort with an accuracy of 79.2%.

Conclusion

DNAm biomarkers with clinical utility for predicting food challenge outcomes are readily detectable in blood. The development of this technology in detailed follow-up studies will yield highly innovative diagnostic assays.

Section snippets

Sample population

We obtained blood samples from the HealthNuts study in Melbourne, Australia, a population-based study of infant FA.¹¹ These samples were collected from 11- to 15-month-old infants who underwent SPTs to egg white, peanut, and 1 of 2 other foods (cow's milk or shrimp) and had undergone objective OFCs yielding definitive phenotyping data.¹² Although egg allergy is the most common form of FA in early childhood,¹ it has the highest rate of resolution,⁸ whereas peanut allergy is unlikely to resolve⁹

Clinical features of the sample population

For this study, we selected subjects monosensitized to either egg or peanut to represent both the common and severe forms of FA, respectively. Genome-scale methylation analysis was performed on PBMCs from 58 food-sensitized subjects (aged 11-15 months), half of whom were clinically reactive based on OFC results. Thirteen nonsensitized nonallergic control subjects were also assessed. We divided patients into major subgroups according to their food challenge outcome, as shown in Table I.

Discussion

Biomarkers of FA are urgently needed to develop more powerful diagnostic tools that identify bona fide FA against a background of FS. Here we have developed a multivariate classifier model with utility for predicting food challenge outcomes. Different subtypes of FA exist, and we have shown that pattern-finding computational methods perform extremely well when prior knowledge of these subtypes are available. The strength of this approach is rooted in the definitive food challenge outcome data,

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: Supported by the CASS Foundation (SM/11/3647/RMR:DSA), the DHB Foundation (CT21242), and the NHMRC (1072752).

: Disclosure of potential conflict of interest: This study was funded by the CASS Foundation, DHB Foundation, and the National Health and Medical Research Council, Australia's leading expert body promoting the development and maintenance of public and individual health standards. S. Prescott has received compensation for board membership from Danone Nutricia and the Nestlè Nutrition Institute, has received payment for delivering lectures from Danone Nutricia and the Nestlè Nutrition Institute, and receives royalties from UpToDate. M. L. K. Tang has received compensation for board membership from Danone Nutricia and the Nestlè Nutrition Institute; has received payment for delivering lectures from Danone Nutricia and the Nestlè Nutrition Institute; and has received compensation for travel and other meeting-related expenses from APARPI. A.-L. Ponsonby is employed by the NHMRC, from which she has also received or has grants pending. K. J. Allen has received consultancy fees from Nutricia, Danone, Nestlè, Aspen, and Alphapharm. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: These author contributed equally to this work.

View full text

Mechanisms of allergy and clinical immunologyBlood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants

Background

Objective

Methods

Results

Conclusion

Section snippets

Sample population

Clinical features of the sample population

Discussion

J Reprod Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants

J Allergy Clin Immunol

Food allergy: riding the second wave of the allergy epidemic

Pediatr Allergy Immunol

Diagnosis of food allergies: the impact of oral food challenge testing

Asia Pac Allergy

Food allergy and anaphylaxis in pediatrics: update 2010-2012

Pediatr Allergy Immunol

Epigenome-wide association studies for common human diseases

Nat Rev Genet

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Epigenetics

Mechanisms of allergy and clinical immunology
Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants