Marijn C Visschedijk1,2, Lieke M Spekhorst1,2, Shih-Chin Cheng3, Ellen S van Loo4, B H Dianne Jansen1, Tjasso Blokzijl1,5, Hyunsuk Kil6, Dirk J de Jong7, Marieke Pierik8, Jeroen P W J Maljaars9, C Janneke van der Woude10, Adriaan A van Bodegraven11, Bas Oldenburg12, Mark Löwenberg13, Vincent B Nieuwenhuijs14, Floris Imhann1,2, Suzanne van Sommeren1,2, Rudi Alberts1, Ramnik J Xavier3, Gerard Dijkstra1, Klaas Nico Faber1,5, C Marcelo Aldaz6, Rinse K Weersma1, Eleonora A M Festen1,2. 1. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands. 2. Department of Genetics, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands. 3. Broad Institute of Harvard and MIT, Boston, USA. 4. Department of Surgery, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands. 5. Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 6. Department of Epigenetics and Molecular Carcinogenesis, Science Park, The University of Texas M.D. Anderson Cancer Centre, Smithville, USA. 7. Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 8. Division of Gastroenterology and Hepatology, University Medical Centre Maastricht, Maastricht, The Netherlands. 9. Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands. 10. Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, The Netherlands. 11. Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands. 12. Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands. 13. Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands. 14. Department of Surgery, Isala Clinics, Zwolle, The Netherlands.
Abstract
Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD. Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-β and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-β compared to patients homozygous for the wild-type [G] allele [p = 0.0079]. Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.
Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD. Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-β and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-β compared to patients homozygous for the wild-type [G] allele [p = 0.0079]. Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.
Authors: Calen A Steiner; Jeffrey A Berinstein; Jeremy Louissaint; Peter D R Higgins; Jason R Spence; Carol Shannon; Cathy Lu; Ryan W Stidham; Joel G Fletcher; David H Bruining; Brian G Feagan; Vipul Jairath; Mark E Baker; Dominik Bettenworth; Florian Rieder Journal: Clin Gastroenterol Hepatol Date: 2021-06-02 Impact factor: 11.382
Authors: Floris Imhann; K J Van der Velde; R Barbieri; R Alberts; M D Voskuil; A Vich Vila; V Collij; L M Spekhorst; K W J Van der Sloot; V Peters; H M Van Dullemen; M C Visschedijk; E A M Festen; M A Swertz; G Dijkstra; R K Weersma Journal: BMC Gastroenterol Date: 2019-01-08 Impact factor: 3.067