Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease

Marijn C Visschedijk, Lieke M Spekhorst, Shih-Chin Cheng, Ellen S van Loo, B H Dianne Jansen, Tjasso Blokzijl, Hyunsuk Kil, Dirk J de Jong, Marieke Pierik, Jeroen P W J Maljaars, C Janneke van der Woude, Adriaan A van Bodegraven, Bas Oldenburg, Mark Löwenberg, Vincent B Nieuwenhuijs, Floris Imhann, Suzanne van Sommeren, Rudi Alberts, Ramnik J Xavier, Gerard DijkstraKlaas Nico Faber, C Marcelo Aldaz, Rinse K Weersma, Eleonora A M Festen

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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-beta 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-beta 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.

Original languageEnglish
Pages (from-to)582-588
Number of pages7
JournalJournal of Crohn's and Colitis
Volume12
Issue number5
Early online date19-Jan-2018
DOIs
Publication statusPublished - May-2018

Keywords

  • Crohn's disease
  • fibrosis
  • genetics
  • INFLAMMATORY-BOWEL-DISEASE
  • WIDE ASSOCIATION
  • INTESTINAL FIBROSIS
  • RISK
  • LOCI
  • SUSCEPTIBILITY
  • IDENTIFICATION
  • VISUALIZATION
  • PHENOTYPES

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