Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome.
ATG16L1
DGKZ
RBM8A
FPIES
NGS
exomes
food allergy
Journal
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
ISSN: 1365-2222
Titre abrégé: Clin Exp Allergy
Pays: England
ID NLM: 8906443
Informations de publication
Date de publication:
30 Sep 2024
30 Sep 2024
Historique:
received:
09
07
2024
accepted:
01
09
2024
medline:
1
10
2024
pubmed:
1
10
2024
entrez:
30
9
2024
Statut:
aheadofprint
Résumé
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. Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study. 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-β 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). 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.
Sections du résumé
BACKGROUND
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
METHODS
Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study.
RESULTS
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-β 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
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : TRINEO-PI22/00162
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : DIAVIR-DTS19/00049
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : Resvi-Omics-PI19/01039
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : ReSVinext-PI16/01569
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : Enterogen-PI19/01090
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : OMI-COVI-VAC-PI22/00406
Organisme : Strategic Health Action, "Instituto de Salud Carlos III" (ISCIII) cofinanciados FEDER
ID : BIO-FPIES-PI19/00497
Organisme : Axencia Galega de Innovación (GAIN)
ID : IN607B2020/08
Organisme : Axencia Galega de Innovación (GAIN)
ID : IN607A2023/02
Organisme : Axencia Galega de Innovación (GAIN)
ID : IN607D2024/06
Organisme : Axencia Galega de Innovación (GAIN)
ID : GENCOVID-IN845D2020/23
Organisme : Axencia Galega de Innovación (GAIN)
ID : IIN607A2021/05
Organisme : Agencia Gallega de Conocimiento en Salud (ACIS)
ID : BI-BACVIR
Organisme : Agencia Gallega de Conocimiento en Salud (ACIS)
ID : CovidPhy-SA304C
Organisme : Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI)
ID : PID2022-142156OB-I00
Organisme : Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union
ID : CP23/00080
Organisme : Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias
ID : CB21/06/00103
Informations de copyright
© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.
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