| Title: |
DOP29 Elevation of a novel blood-based gene signature in a severe Crohn’s disease (CD) subtype preceding surgery defines and predicts a post-surgical decrease in pro-inflammatory pathway activation |
| Authors: |
Gonsky, R; Fleshner, P; Botwin, G; Biener-Ramanujan, E; McGovern, D; Targan, S |
| Source: |
Journal of Crohn's and Colitis ; volume 14, issue Supplement_1, page S068-S069 ; ISSN 1873-9946 1876-4479 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2020 |
| Description: |
Background CD is defined by transmural inflammation leading to inflammatory, stricturing and/or penetrating phenotypes. Identifying underlying molecular pathways and distinct disease subsets is critical for improved prognostics, therapeutics and biomarker discovery. Methods CD3+ T cells were purified from paired blood and mucosal tissue from 101 CD and 17 non-IBD subjects requiring surgery. Longitudinal samples (n = 30) were collected 4–13 mo. post-surgery. Expression profiles were generated by RNAseq, T-cell subset deconvolution by xCell and transcriptome-wide associations (TWAS) using TWAS-hub. Results Unsupervised clustering of peripheral T-cell gene expression at surgery revealed 2 CD profiles: Expression from cluster1, labelled CD-PBT (63%), clustered tightly with the non-IBD group. In cluster2, expression shifted from a peripheral toward a mucosal profile, labelled CD-PBmu(cosal) (37%). CD-PBmu was defined by differentially expressed genes (DEG) (1944 DEG, p < 0.001) regulating cell migration and adhesion pathways and a distinct T-cell subset composition associated with stricturing disease (p=0.03), increased resected bowel length (p=0.036) and post-op recurrence (p=0.01). There were no significant differences in disease location/behaviour. Independent validation (5 public datasets) confirmed the CD-PBmu signature in data from whole blood (CD patients failing anti-TNF therapy, n = 204) and the mucosal-like expression profile in data from ileal tissue (paediatric CD patients, studies n = 751). A defining feature of CD-PBmu, validated in a separate CD cohort (n = 19), was decreased pro-inflammatory cytokine/chemokine and adhesion molecule expression following surgery (900 DEG, p < 0.001). No post-surgery change in expression was detected in CD-PBT. A 44-gene classifier was identified to enable clinical application. The classifier accurately detected the CD-PBmu patient subtype, correlated with the altered composition of peripheral T-cell subsets and overlapped with IBD associated ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/ecco-jcc/jjz203.068 |
| Availability: |
https://doi.org/10.1093/ecco-jcc/jjz203.068; http://academic.oup.com/ecco-jcc/article-pdf/14/Supplement_1/S068/31850627/jjz203.068.pdf |
| Rights: |
https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model |
| Accession Number: |
edsbas.4F9C81F5 |
| Database: |
BASE |