Multi-omics analysis reveals vitamin D metabolism, hyper-IgE genes, and epithelial barrier dysfunction in hazelnut allergy

ABSTRACT Background: Hazelnut allergy is a major cause of food-induced anaphylaxis yet remains poorly defined at the molecular level. Objective: We aimed to identify molecular differences between individuals with primary hazelnut allergy and nonallergic controls by investigating a comprehensive spectrum of omics profiles in immune cells. Methods: We analysed DNA methylation, transcriptomic and proteomic profiles in hazelnut-stimulated and unstimulated immune cells. Results: Across analyses, we identified 80 differentially methylated signatures, 125 differentially expressed genes, and 11 differentially secreted proteins associated with hazelnut allergy. DNA methylation signatures were highly concordant between unstimulated and stimulated conditions, consistent with stable epigenetic remodelling. Key findings implicated ZNF341 , associated with a rare monogenic hyper-IgE syndrome, and ARL2 , both linked to STAT3-mediated IgE dysregulation. Additionally, we identified a differentially methylated region (DMR) overlapping the T Helper Type 2 Locus Control Region Associated RNA ( TH2LCRR ) in the cytokine gene cluster, suggesting an epigenetic mechanism contributing to IL-5 and IL-13 upregulation. Antigen stimulation was required to reveal hazelnut-specific transcriptional and proteomic signals. Integration of these data demonstrated that IL-5 expression could distinguish both groups. We identified signals in epithelial barrier genes of the gut and skin ( TRIM31 , TRIM40 , CDSN ), activation of the vitamin D pathway ( CYP27B1 , IL32 ), and nominate additional signals ( PHACTR1, MFHAS1, SPRED2, GALNT5/GALNTL4, NSMCE1-DT ) for follow-up. Conclusion: Our study confirms type-2 cytokines, FcεRI, and JAK–STAT signalling and uncovers novel links to monogenic hyper-IgE syndrome, activation of vitamin-D pathways, and gut/skin barrier genes, yielding a catalogue of candidate biomarkers for mechanistic studies and prospective validation. Key messages Antigen-specific multi-omics analysis confirms JAK-STAT and Th2 control pathways, with IL-5 emerging as a key marker distinguishing hazelnut-allergic from nonallergic individuals. Epigenetic and transcriptomic analysis points to roles for vitamin D metabolism, hyper-IgE-associated genes, and epithelial barrier dysfunction in hazelnut allergy This first antigen-specific methylation and multi-omics discovery study in hazelnut allergy provides candidate pathways and genes to guide future studies Capsule summary This antigen-specific multi-omics study confirms JAK-STAT/Th2 control pathways, pinpoints the IL-5 response as biomarker distinguishing hazelnut allergy, implicates vitamin D metabolism, hyper-IgE genes, and epithelial barrier dysfunction, and delivers additional candidate genes to guide future research.