Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.
Authors
Peters, James
Savinykh, Natalia
Siegel, Richard M
Publication Date
2018-09Journal Title
PLoS Genet
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Volume
14
Issue
9
Pages
e1007458
Language
eng
Type
Article
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Richard, A., Peters, J., Savinykh, N., Lee, J., Hawley, E. T., Meylan, F., Siegel, R. M., et al. (2018). Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.. PLoS Genet, 14 (9), e1007458. https://doi.org/10.1371/journal.pgen.1007458
Abstract
Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD.
Keywords
Monocytes, Cells, Cultured, Macrophages, Humans, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Haplotypes, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Adult, Middle Aged, Female, Male, Tumor Necrosis Factor Ligand Superfamily Member 15, Young Adult, Primary Cell Culture
Sponsorship
Wellcome Trust (083650/Z/07/Z)
Medical Research Council (MR/L019027/1)
British Heart Foundation (None)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1007458
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279608
Rights
CC0 1.0 Universal (CC0 1.0)Public Domain Dedication
Licence URL: https://creativecommons.org/publicdomain/zero/1.0/
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