Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension.
Bayes Theorem
Biopsy
Case-Control Studies
Colitis, Ulcerative
/ genetics
Colon
/ metabolism
Cross-Sectional Studies
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Humans
Patient Acuity
Poly(ADP-ribose) Polymerases
/ genetics
Predictive Value of Tests
Sequence Analysis, RNA
Signal Transduction
Transcriptome
Disease Extension
Interferon Signaling
Molecular
PARP14
UC
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
23
11
2020
revised:
27
08
2021
accepted:
27
08
2021
pubmed:
5
9
2021
medline:
19
1
2022
entrez:
4
9
2021
Statut:
ppublish
Résumé
Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension. We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments. Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended. Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.
Sections du résumé
BACKGROUND AND AIMS
Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.
METHODS
We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments.
RESULTS
Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient's most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended.
CONCLUSION
Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.
Identifiants
pubmed: 34480882
pii: S0016-5085(21)03472-7
doi: 10.1053/j.gastro.2021.08.053
pmc: PMC8640960
mid: NIHMS1754842
pii:
doi:
Substances chimiques
PARP14 protein, human
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1953-1968.e15Subventions
Organisme : NIDDK NIH HHS
ID : K23 DK111995
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK122532
Pays : United States
Informations de copyright
Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.
Références
J Intern Med. 2011 Sep;270(3):229-36
pubmed: 21332844
Nature. 2012 Nov 1;491(7422):119-24
pubmed: 23128233
Hum Mol Genet. 2020 Sep 30;29(R1):R51-R58
pubmed: 32588873
Nature. 2019 Nov;575(7783):512-518
pubmed: 31597160
Eur Cytokine Netw. 2013 Jul-Sep;24(3):130-8
pubmed: 24197332
Oncogene. 2017 Nov 2;36(44):6097-6108
pubmed: 28671670
Nat Commun. 2016 Oct 31;7:12849
pubmed: 27796300
Circ Res. 2018 Jan 19;122(2):231-245
pubmed: 29233846
J Crohns Colitis. 2017 Dec 4;11(12):1491-1503
pubmed: 25306501
BMC Bioinformatics. 2013 Jan 16;14:7
pubmed: 23323831
Gastroenterology. 2006 Jun;130(7):2060-73
pubmed: 16762629
Matrix Biol. 2020 May;87:11-25
pubmed: 31422156
J Immunol. 2007 Jan 15;178(2):1122-35
pubmed: 17202376
Gut. 2018 Jan;67(1):43-52
pubmed: 27802155
Aliment Pharmacol Ther. 2017 Jun;45(12):1481-1492
pubmed: 28449361
J Clin Invest. 2011 Oct;121(10):4170-9
pubmed: 21946256
Nat Genet. 2017 Oct;49(10):1517-1521
pubmed: 28805827
Gastroenterology. 1997 Jul;113(1):107-17
pubmed: 9207268
J Crohns Colitis. 2017 Oct 1;11(10):1200-1204
pubmed: 28486626
Sci Rep. 2020 Jan 15;10(1):323
pubmed: 31941986
Lancet. 2017 Apr 29;389(10080):1756-1770
pubmed: 27914657
PLoS Comput Biol. 2014 Jul 24;10(7):e1003731
pubmed: 25058159
BMC Gastroenterol. 2019 Jan 10;19(1):7
pubmed: 30630426
Gastroenterology. 2021 Jan;160(1):232-244.e7
pubmed: 32814113
J Immunol. 2018 Apr 1;200(7):2439-2454
pubmed: 29500242
Nat Med. 2017 May;23(5):579-589
pubmed: 28368383
Gut. 2021 Feb;70(2):418-426
pubmed: 32699100
Cancer Cell. 2013 Aug 12;24(2):229-41
pubmed: 23871637
Nat Commun. 2019 Jan 3;10(1):38
pubmed: 30604764
Can J Gastroenterol. 2005 Sep;19 Suppl A:5A-36A
pubmed: 16151544
Nat Genet. 2017 Oct;49(10):1437-1449
pubmed: 28892060
Immunity. 2014 Feb 20;40(2):274-88
pubmed: 24530056
Cell. 2019 Jul 25;178(3):714-730.e22
pubmed: 31348891
BMJ Open. 2018 Dec 5;8(12):e026767
pubmed: 30523133
Nat Rev Gastroenterol Hepatol. 2019 May;16(5):296-311
pubmed: 30787446
J Clin Invest. 2019 Nov 1;129(11):4691-4707
pubmed: 31566580
Cell. 2019 Sep 5;178(6):1493-1508.e20
pubmed: 31474370
Gastroenterology. 2021 Jan;160(1):287-301.e20
pubmed: 32980345
Gastroenterol Clin Biol. 1995 Nov;19(11):867-70
pubmed: 8746043
PLoS Genet. 2019 Dec 17;15(12):e1008482
pubmed: 31846472
BMC Immunol. 2019 Nov 12;20(1):42
pubmed: 31718550
Nat Immunol. 2015 Dec;16(12):1215-27
pubmed: 26479788
Oncol Lett. 2019 Oct;18(4):3954-3962
pubmed: 31579078
Front Immunol. 2017 Mar 14;8:258
pubmed: 28352268