Scientific Study

Background: Unexpected 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. Objectives: To expand mechanistic understanding of reaction severity in peanut allergy. Methods: We 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. 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. Results: We 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 three groups of interacting key node CpGs and peanut severity genes encompassing immune response, chemotaxis, and regulation of macroautophagy. Additionally, we found that gene expression of PHACTR1 and ZNF121 causally mediate 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. Conclusions: Our findings enhance current mechanistic understanding of the genetic and epigenetic architecture of reaction severity in peanut allergy.