Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Lange, Katrina M. de; Moutsianas, Loukas; Lee, James C.; Lamb, Christopher A; Luo, Yang; Kennedy, Nicholas A; Jostins, Luke; Dl, Rice; Gutiérrez-Achury, Javier; Ji, Sun‐Gou; Heap, Graham A.; Nimmo, Elaine R.; Edwards, Cathryn; Henderson, Paul; Mowat, Craig; Sanderson, Jeremy; Satsangi, Jack; Simmons, Alison; Wilson, David C.; Tremelling, Mark; Hart, Ailsa; Mathew, Christopher G.; Newman, William G.; Parkes, Miles; Lees, Charlie W; Uhlig, Holm H.; Hawkey, C. J.; Prescott, Natalie J.; Ahmad, Tariq; Mansfield, John C.; Anderson, Carl A.; Barrett, Jeffrey C.

doi:10.1038/ng.3760

Cited by 998 publications

(759 citation statements)

References 59 publications

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“…They are in line with the observation that most risk genes leading to the onset of IBD are involved in the pathways of innate immunity rather than adaptive immunity 8. Macrophages may play a more important role in IBD pathophysiology as compared with the T-cells compartment.…”

supporting

confidence: 85%

Mechanism of action of vedolizumab: do we really understand it?

Rogler

2018

Gut

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supporting

confidence: 85%

Mechanism of action of vedolizumab: do we really understand it?

Rogler

2018

Gut

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“…ICAM1 was recently identified as a candidate gene at an IBD susceptibility locus, with upregulated gene expression associated with the disease-risk variant. 33 ICAM1 is a transmembrane adhesion protein commonly expressed by vascular endothelium and leukocytes. Binding of ICAM1 to the LFA1 receptor on T cells facilitates and stabilizes cell-cell interactions.…”

Section: Resultsmentioning

confidence: 99%

“…Altered expression of RNASET2 , both increased and decreased, is associated with various diseases, including cancers 25–27 and autoimmune diseases, 29, 40, 43, 44 suggesting a role for RNASET2 in host immune responses. RNASET2 expression is downregulated and likely involved in the pathogenesis of colorectal cancer, 33 melanoma, 19 anaplastic large cell lymphoma 34 and non-Hodgkin lymphoma. 27 In human ovarian cancer overexpression of RNASET2 is associated with tumor suppression and is believed to modulate tumor micro-environment cross-talk through recruitment of monocyte/macrophages to the tumor itself.…”

Section: Discussionmentioning

confidence: 99%

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn’s Disease

et al. 2017

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Background & Aims Variants in the tumor necrosis factor superfamily member 15 gene (TNFSF15, also called TL1A) have been associated with risk for inflammatory bowel diseases (IBD). TL1A affects expression of multiple cytokines to promote mucosal inflammation. Little is known about the TL1A-response pathways that regulate cytokine expression. We investigated T-cell gene expression patterns to determine the mechanisms by which TL1A regulates cytokine production, and whether these associate with outcomes of patients with Crohn’s disease (CD). Methods Peripheral T cells isolated from normal donors were cultured with TL1A. We performed gene expression profile analysis, by RNA sequencing, of subsets of interferon gamma (IFNG)-producing and non-producing cells, purified by flow cytometry. Unsupervised hierarchical clustering analysis was used to identify gene expression differences between these subsets. Ribonuclease T2 gene (RNASET2) expression and methylation were assessed by quantitative trait loci analyses. Clinical characteristics of patients (complications, resistance to therapy, recurrence time) were associated with single nucleotide polymorphisms in RNASET2. We performed motif screening to identify polymorphisms that disrupt transcription factor binding sites. Levels of RNASET2 were knocked down with small interfering RNA in CD4+ T cells and the effect on protein expression was determined by proteomic analysis and cytokine production. Cell aggregation was measured by flow cytometry. Results We identified 764 genes with at least a 2-fold difference in TL1A-mediated expression between IFNG-secreting and non-secreting T cells (P<1 × 10−5). Many of these genes were located near IBD susceptibility variants. RNASET2 was the only IBD risk-associated gene with greater than 5-fold downregulation in the IFNG-secreting subset. RNASET2 disease risk variants were associated with decreased expression in peripheral and mucosal tissues and DNA hypermethylation in CD patients requiring surgical intervention. RNASET2 disease risk variants were associated in CD patients with more complicated disease or resistance to therapy, defined in part by failed response to treatment, increased length of intestinal resection, shorter time to repeat surgery, and high Rutgeerts score (>2) in post-operative endoscopy. The RNASET2 variant rs2149092 was predicted to disrupt a consensus binding site for the transcription factor ETS within an enhancer region. Expression of RNASET2 correlated with expression of ETS. RNASET2 knockdown in T cells increased expression of IFNG and ICAM1 and induced T cells aggregation. A blocking antibody against LFA1, disrupting the LFA1-ICAM1 interaction, reduced T-cell production of IFNG. Conclusions We identified decreased expression of RNASET2 as a component of TL1A-mediated increase in production of IFNG and as a potential biomarker for patients with severe CD. Further study of the role of RNASET2 in regulating mucosal inflammation may lead to development of novel therapeutic targets.

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“…This means that some SNPs will only affect pathogenicity on, for example, inflammation or during infection. These context-specific eQTLs are now used in search of causative genes in GWAS 15. A recent study has identified eQTLs in ileal biopsies from patients in different stages of CD (healthy, complication-free disease and disease progression with stricturing or penetrating disease).…”

Section: Regulatory Information Creates Novel Insight In Cell Types Amentioning

confidence: 99%

Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

Meddens

List

Nieuwenhuis

et al. 2019

Gut

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Genome-wide association studies have identified over 200 loci associated with IBD. We and others have recently shown that, in addition to variants in protein-coding genes, the majority of the associated loci are related to DNA regulatory elements (DREs). These findings add a dimension to the already complex genetic background of IBD. In this review we summarise the existing evidence on the role of DREs in IBD. We discuss how epigenetic research can be used in candidate gene approaches that take non-coding variants into account and can help to pinpoint the essential pathways and cell types in the pathogenesis of IBD. Despite the increased level of genetic complexity, these findings can contribute to novel therapeutic options that target transcription factor binding and enhancer activity. Finally, we summarise the future directions and challenges of this emerging field.

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Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Cited by 998 publications

References 59 publications

Mechanism of action of vedolizumab: do we really understand it?

Mechanism of action of vedolizumab: do we really understand it?

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn’s Disease

Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential

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