Dual transcriptomic and epigenomic study of reaction severity in peanut-allergic children - 06/04/20
Abstract |
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 |
We sought 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 (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.
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 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.
Conclusions |
Our findings enhance current mechanistic understanding of the genetic and epigenetic architecture of reaction severity in peanut allergy.
El texto completo de este artículo está disponible en PDF.Graphical abstract |
Key words : Food allergy, peanut allergy, reaction severity, transcriptome, epigenome, integrated network, causal mediation
Abbreviations used : eCpG, FDR, GO, NF-κB, RNAseq, sIgE, SPT
Esquema
| This study was supported by the National Institutes of Health (grant nos. R01AI118833, U19AI136053, U19AI066738, and U01AI066560) and the Mindich Child Health and Development Institute at Mount Sinai. The project was also supported by National Jewish (grant no. UL1 TR-002535), Mount Sinai (grant no. UL1 TR-000067), University of Arkansas (grant no. UL1 TR-000039), University of North Carolina (grant no. UL1 TR-000083), and Johns Hopkins (grant no. UL1 TR-000424) from the National Center for Research Resources, a component of the National Institutes of Health. The funding bodies had no role in the collection, analysis, or interpretation of data, or the writing of the manuscript. |
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| Disclosure of potential conflict of interests: The authors declare that they have no relevant conflicts of interests. |
Vol 145 - N° 4
P. 1219-1230 - avril 2020 Regresar al número
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