Genomic and expression analyses identify a disease-modifying variant for Fibrostenotic Crohn's disease
Visschedijk, Marijn C.; Spekhorst, Lieke M.; Cheng, Shih Chin; van Loo, Ellen S.; Dianne Jansen, B. H.; Blokzijl, Tjasso; Kil, Hyunsuk; de Jong, Dirk J.; Pierik, Marieke; Maljaars, Jeroen P.W.J.; van der Woude, C. Janneke; van Bodegraven, Adriaan A.; Oldenburg, Bas; Löwenberg, Mark; Nieuwenhuijs, Vincent B.; Imhann, Floris; van Sommeren, Suzanne; Alberts, Rudi; Xavier, Ramnik J.; Dijkstra, Gerard; Faber, Klaas Nico; Marcelo Aldaz, C.; Weersma, Rinse K.; Festen, Eleonora A.M.
(2018) Journal of Crohn's & Colitis, volume 12, issue 5, pp. 582 - 588
(Article)
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
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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-ß 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-ß 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 diseasemodifying 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.
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Keywords: Crohn's disease, Fibrosis, Genetics, Gastroenterology
ISSN: 1873-9946
Publisher: Elsevier
Note: Publisher Copyright: © 2018 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved.
(Peer reviewed)