Multi-Omics Analysis Reveals Vitamin D Metabolism, Hyper-IgE Genes, and Epithelial Barrier Dysfunction in Hazelnut Allergy

Hazelnut allergy is a major cause of food-induced anaphylaxis yet remains poorly defined at the molecular level. 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.

We analysed DNA methylation, transcriptomic, and proteomic profiles in hazelnut-stimulated and unstimulated immune cells.

Across analyses, we identified 87 differentially methylated signatures, 125 unique differentially expressed genes, and 11 unique differentially secreted proteins associated with hazelnut allergy. DNA methylation signatures were largely preserved irrespective of antigen stimulation, indicating stable epigenetic remodelling. Key findings implicated ZNF341, associated with a rare monogenic hyper-IgE syndrome, and ARL2, both linked to STAT3-mediated IgE dysregulation. We identified a hypermethylated region overlapping 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. Moreover, integrated analysis of all multi-omics data revealed prominent innate immune activation programs involving antimicrobial, antiviral, and cytokine-mediated inflammatory responses. Finally, we identified signals in epithelial barrier genes of the gut and skin (TRIM31, TRIM40, CDSN), activation of the vitamin D pathway (CYP27B1, IL32), and nominated additional signals (PHACTR1, MFHAS1, SPRED2, NSMCE1-DT) for follow-up.

This study provides the first antigen-specific multi-omics characterization of hazelnut allergy, confirming coordinated alterations in type 2-immunity and uncovering novel links to monogenic hyper-IgE syndrome, innate inflammatory pathways, activation of vitamin-D pathways, and gut/skin barrier genes, yielding a catalogue of candidate biomarkers for mechanistic studies and prospective validation.