Yael Haberman1,2, Phillip Minar1, Rebekah Karns1, Phillip J Dexheimer1, Sudhir Ghandikota3, Samuel Tegge1, Daniel Shapiro1, Brianne Shuler1, Suresh Venkateswaran4, Tzipi Braun2, Allison Ta1, Thomas D Walters5, Robert N Baldassano6, Joshua D Noe7, Joel Rosh8, James Markowitz9, Jennifer L Dotson10, David R Mack11, Richard Kellermayer12, Anne M Griffiths5, Melvin B Heyman13, Susan S Baker14, Dedrick Moulton15, Ashish S Patel16, Ajay S Gulati17, Steven J Steiner18, Neal LeLeiko19, Anthony Otley20, Maria Oliva-Hemker21, David Ziring22, Ranjana Gokhale23, Sandra Kim24, Stephen L Guthery25, Stanley A Cohen26, Scott Snapper27, Bruce J Aronow1, Michael Stephens28, Greg Gibson29, Jonathan R Dillman1, Marla Dubinsky30, Jeffrey S Hyams31, Subra Kugathasan4, Anil G Jegga1, Lee A Denson1. 1. Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA. 2. Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Israel. 3. University of Cincinnati College of Engineering, Cincinnati, OH, USA. 4. Emory University, Atlanta, GA, USA. 5. Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. 6. The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 7. Medical College of Wisconsin, Milwaukee, WI. USA. 8. Goryeb Children's Hospital/Atlantic Health, Morristown, NJ, USA. 9. Cohen Children's Medical Center of New York, New Hyde Park, NY, USA. 10. Nationwide Children's Hospital, Columbus, OH, USA. 11. Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada. 12. Texas Children's Hospital, Baylor College School of Medicine, Houston, TX, USA. 13. University of California San Francisco, San Francisco, CA, USA. 14. University at Buffalo, Buffalo, NY, USA. 15. Monroe Carell Jr Children's Hospital, Nashville, TN. 16. UT Southwestern Medical Center at Dallas, Dallas, TX, USA. 17. University of North Carolina, Chapel Hill, NC, USA. 18. Riley Children's Hospital, Indianapolis, IN, USA. 19. Hasbro Children's Hospital, Providence, RI, USA. 20. IWK Health Centre, Halifax, NS, Canada. 21. John Hopkins University, Baltimore, MD, USA. 22. Cedars-Sinai Medical Center, Los Angeles, CA, USA. 23. University of Chicago Comer Children's Hospital, Chicago, IL, USA. 24. Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. 25. University of Utah and Intermountain Primary Children's Hospital, Salt Lake City, UT, USA. 26. Children's Center for Digestive Health Medicine, Atlanta, GA, USA. 27. Children's Hospital - Boston, Boston, MA, USA. 28. Mayo clinic, Rochester, MN, USA. 29. Georgia Institute of Technology, Atlanta, Georgia, USA. 30. Mount Sinai Hospital New York, NY, USA. 31. Connecticut Children's Medical Center, Hartford, CT, USA.
Abstract
BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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