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

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. We performed a within-case analysis comparing "extreme phenotypes" using the Immunochip and replication of the top 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. Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007, (P = 6.09 × 10-11), located on chromosome 16, in lncRNA RP11-679B19.1, a 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). 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