Carmen Argmann1, Minami Tokuyama2, Ryan C Ungaro2, Ruiqi Huang3, Ruixue Hou3, Sakteesh Gurunathan2, Roman Kosoy4, Antonio Di'Narzo5, Wenhui Wang4, Bojan Losic4, Haritz Irizar6, Lauren Peters4, Aleksandar Stojmirovic7, Gabrielle Wei4, Phillip H Comella4, Mark Curran7, Carrie Brodmerkel7, Joshua R Friedman7, Ke Hao5, Eric E Schadt5, Jun Zhu5, Judy Cho2, Noam Harpaz8, Marla C Dubinsky2, Bruce E Sands2, Andrew Kasarskis9, Saurabh Mehandru2, Jean-Frederic Colombel2, Mayte Suárez-Fariñas10. 1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, New York, New York. Electronic address: carmen.argmann@mssm.edu. 2. The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, New York, New York. 5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, New York, New York; Sema4, Stamford, Connecticut. 6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Janssen R&D, Spring House, Pennsylvania. 8. The Dr. Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York. 9. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Icahn Institute for Data Science and Genomic Technology, New York, New York; Sema4, Stamford, Connecticut; Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. 10. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Center for Biostatistics, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: mayte.suarez-farinas@mssm.edu.
Abstract
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.
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.
Authors: A Mälarstig; A Silveira; D Wågsäter; J Öhrvik; A Bäcklund; A Samnegård; M Khademi; M-L Hellenius; K Leander; T Olsson; M Uhlén; U de Faire; P Eriksson; A Hamsten Journal: J Intern Med Date: 2011-03-21 Impact factor: 8.989
Authors: Marco F Morini; Costanza Giampietro; Monica Corada; Federica Pisati; Elisa Lavarone; Sara I Cunha; Lei L Conze; Nicola O'Reilly; Dhira Joshi; Svend Kjaer; Roger George; Emma Nye; Anqi Ma; Jian Jin; Richard Mitter; Michela Lupia; Ugo Cavallaro; Diego Pasini; Dinis P Calado; Elisabetta Dejana; Andrea Taddei Journal: Circ Res Date: 2017-12-12 Impact factor: 17.367
Authors: P Ramachandran; R Dobie; J R Wilson-Kanamori; E F Dora; B E P Henderson; N T Luu; J R Portman; K P Matchett; M Brice; J A Marwick; R S Taylor; M Efremova; R Vento-Tormo; N O Carragher; T J Kendall; J A Fallowfield; E M Harrison; D J Mole; S J Wigmore; P N Newsome; C J Weston; J P Iredale; F Tacke; J W Pollard; C P Ponting; J C Marioni; S A Teichmann; N C Henderson Journal: Nature Date: 2019-10-09 Impact factor: 49.962
Authors: Luke Jostins; Stephan Ripke; Rinse K Weersma; Richard H Duerr; Dermot P McGovern; Ken Y Hui; James C Lee; L Philip Schumm; Yashoda Sharma; Carl A Anderson; Jonah Essers; Mitja Mitrovic; Kaida Ning; Isabelle Cleynen; Emilie Theatre; Sarah L Spain; Soumya Raychaudhuri; Philippe Goyette; Zhi Wei; Clara Abraham; Jean-Paul Achkar; Tariq Ahmad; Leila Amininejad; Ashwin N Ananthakrishnan; Vibeke Andersen; Jane M Andrews; Leonard Baidoo; Tobias Balschun; Peter A Bampton; Alain Bitton; Gabrielle Boucher; Stephan Brand; Carsten Büning; Ariella Cohain; Sven Cichon; Mauro D'Amato; Dirk De Jong; Kathy L Devaney; Marla Dubinsky; Cathryn Edwards; David Ellinghaus; Lynnette R Ferguson; Denis Franchimont; Karin Fransen; Richard Gearry; Michel Georges; Christian Gieger; Jürgen Glas; Talin Haritunians; Ailsa Hart; Chris Hawkey; Matija Hedl; Xinli Hu; Tom H Karlsen; Limas Kupcinskas; Subra Kugathasan; Anna Latiano; Debby Laukens; Ian C Lawrance; Charlie W Lees; Edouard Louis; Gillian Mahy; John Mansfield; Angharad R Morgan; Craig Mowat; William Newman; Orazio Palmieri; Cyriel Y Ponsioen; Uros Potocnik; Natalie J Prescott; Miguel Regueiro; Jerome I Rotter; Richard K Russell; Jeremy D Sanderson; Miquel Sans; Jack Satsangi; Stefan Schreiber; Lisa A Simms; Jurgita Sventoraityte; Stephan R Targan; Kent D Taylor; Mark Tremelling; Hein W Verspaget; Martine De Vos; Cisca Wijmenga; David C Wilson; Juliane Winkelmann; Ramnik J Xavier; Sebastian Zeissig; Bin Zhang; Clarence K Zhang; Hongyu Zhao; Mark S Silverberg; Vito Annese; Hakon Hakonarson; Steven R Brant; Graham Radford-Smith; Christopher G Mathew; John D Rioux; Eric E Schadt; Mark J Daly; Andre Franke; Miles Parkes; Severine Vermeire; Jeffrey C Barrett; Judy H Cho Journal: Nature Date: 2012-11-01 Impact factor: 49.962
Authors: K A Khan; A J Naylor; A Khan; P J Noy; M Mambretti; P Lodhia; J Athwal; A Korzystka; C D Buckley; B E Willcox; F Mohammed; R Bicknell Journal: Oncogene Date: 2017-07-03 Impact factor: 9.867