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Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions.

ABSTRACT: Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpression networks for acute-phase response and pro-inflammatory processes. Key driver analysis identifies six genes (LTB4R, PADI4, IL1R2, PPP1R3D, KLHL2, and ECHDC3) predicted to causally modulate the state of coregulated networks in response to peanut. Leukocyte deconvolution analysis identifies changes in neutrophil, naive CD4+ T cell, and macrophage populations during peanut challenge. Analyses in 21 additional peanut allergic subjects replicate major findings. These results highlight key genes, biological processes, and cell types that can be targeted for mechanistic study and therapeutic targeting of peanut allergy.

SUBMITTER: Watson CT

PROVIDER: S-EPMC5715016 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions.

Watson C T CT Cohain A T AT Griffin R S RS Chun Y Y Grishin A A Hacyznska H H Hoffman G E GE Beckmann N D ND Shah H H Dawson P P Henning A A Wood R R Burks A W AW Jones S M SM Leung D Y M DYM Sicherer S S Sampson H A HA Sharp A J AJ Schadt E E EE Bunyavanich S S

Nature communications 20171205 1

Mechanisms driving acute food allergic reactions have not been fully characterized. We profile the dynamic transcriptome of acute peanut allergic reactions using serial peripheral blood samples obtained from 19 children before, during, and after randomized, double-blind, placebo-controlled oral challenges to peanut. We identify genes with changes in expression triggered by peanut, but not placebo, during acute peanut allergic reactions. Network analysis reveals that these genes comprise coexpres ...[more]

PMID: 29203772

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Project description:BackgroundUnexpected allergic reactions to peanut are the most common cause of fatal food-related anaphylaxis. Mechanisms underlying the variable severity of peanut-allergic reactions remain unclear.ObjectivesWe sought to expand mechanistic understanding of reaction severity in peanut allergy.MethodsWe performed an integrated transcriptomic and epigenomic study of peanut-allergic children as they reacted in vivo during double-blind, placebo-controlled peanut challenges. We integrated whole-blood transcriptome and CD4+ T-cell epigenome profiles to identify molecular signatures of reaction severity (ie, how severely a peanut-allergic child reacts when exposed to peanut). A threshold-weighted reaction severity score was calculated for each subject based on symptoms experienced during peanut challenge and the eliciting dose. Through linear mixed effects modeling, network construction, and causal mediation analysis, we identified genes, CpGs, and their interactions that mediate reaction severity. Findings were replicated in an independent cohort.ResultsWe identified 318 genes with changes in expression during the course of reaction associated with reaction severity, and 203 CpG sites with differential DNA methylation associated with reaction severity. After replicating these findings in an independent cohort, we constructed interaction networks with the identified peanut severity genes and CpGs. These analyses and leukocyte deconvolution highlighted neutrophil-mediated immunity. We identified NFKBIA and ARG1 as hubs in the networks and 3 groups of interacting key node CpGs and peanut severity genes encompassing immune response, chemotaxis, and regulation of macroautophagy. In addition, we found that gene expression of PHACTR1 and ZNF121 causally mediates the association between methylation at corresponding CpGs and reaction severity, suggesting that methylation may serve as an anchor upon which gene expression modulates reaction severity.ConclusionsOur findings enhance current mechanistic understanding of the genetic and epigenetic architecture of reaction severity in peanut allergy.

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Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions.

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Integrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions.

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