Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients.

Torbjørn Rognes, Henrik M Reims, Børre Fevang, Bente Halvorsen, Pål Aukrust, Knut E A Lundin, Tom H Karlsen, Junbai Wang, Magnar Bjørås, Silje F Jørgensen, Mingyi Yang, Mari Kaarbø, Vegard Myhre

Journal: Journal of clinical immunology 2024;44(6):133

PMID: 38780872

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Abstract

PURPOSE

A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease.

METHODS

DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3).

RESULTS

The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls.

CONCLUSION

This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.

Address: Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Medical Biochemistry, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital and University of Oslo, Lørenskog, Norway.; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.; The Proteomics and Modomics Experimental Core Facility (PROMEC) at Norwegian University of Science and Technology, Trondheim, Norway.; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. [email protected].; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Oslo, Norway. [email protected].

DOI: 10.1007/s10875-024-01726-5

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MeSH Terms: Humans, DNA Methylation, Common Variable Immunodeficiency, Duodenum, Celiac Disease, Female, Male, Adult, Middle Aged, Epigenesis, Genetic, CpG Islands, Promoter Regions, Genetic, Intraepithelial Lymphocytes, Young Adult, Genome-Wide Association Study, 5-Methylcytosine