Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome

Background Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed ligh...

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Authors: Camino-Mera, A, Pardo-Seco, J, Bello, X, Argiz, L, Boyle, RJ, Custovic, A, Herberg, J, Kaforou, M, Arasi, S, Fiocchi, A, Pecora, V, Barni, S, Mori, F, Bracamonte, T, Echeverria, L, O'Valle-Aisa, V, Hernandez-Martinez, NL, Carballeira, I, Garcia, E, Garcia-Magan, C, Moure-Gonzalez, JD, Gonzalez-Delgado, P, Garriga-Baraut, T, Infante, S, Zambrano-Ibarra, G, Tomas-Perez, M, Machinena, A, Pascal, M, Prieto, A, Vazquez-Cortes, S, Fernandez-Rivas, M, Vila, L, Alsina, L, Torres, MJ, Mangone, G, Quirce, S, Martinon-Torres, F, Vazquez-Ortiz, M, Gomez-Carballa, A, Salas, A
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL)
Repository:r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
OAI Identifier:oai:isabial.fundanetsuite.com:p11060
Online Access:https://isabial.portalinvestigacion.com/publicaciones11060
https://onlinelibrary.wiley.com/doi/10.1111/cea.14564
Access Level:Open access
Keyword:DGKZ
exomes
food allergy
FPIES
NGS
RBM8A
Description
Summary:Background Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES. Methods Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study. Results Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-beta signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon). Conclusions This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients.

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