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

Visschedijk, M. C., Spekhorst, L. M., Cheng, S-C., van Loo, E. S., Jansen, B. H. D., Blokzijl, T., Kil, H., de Jong, D. J., Pierik, M., Maljaars, J. P. W. J., van der Woude, C. J., van Bodegraven, A. A., Oldenburg, B., Löwenberg, M., Nieuwenhuijs, V. B., Imhann, F., van Sommeren, S., Alberts, R., Xavier, R. J., Dijkstra, G., Faber, K. N., Aldaz, C. M., Weersma, R. K. & Festen, E. A. M., May-2018, In : Journal of Crohn's and Colitis. 12, 5, p. 582-588 7 p.

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  • Genomic and expression analyses identify a disease modifying variant for fibrostenotic Crohn’s disease

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DOI

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
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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