P719 Identification of a genetic risk variant in the WWOX gene associated with recurrent fibrostenotic Crohn’s disease
M. C. Visschedijk*1, 2, L. M. Spekhorst1, 2, G. Dijkstra1, E. S. van Loo3, D. J. de Jong4, A. E. van der Meulen-de Jong5, H. W. Verspaget5, C. Y. Ponsioen6, V. B. Nieuwenhuijs7, B. Oldenburg8, M. Pierik9, N. K. H. de Boer10, C. J. van der Woude11, F. Imhann1, 2, R. Alberts1, S. van Sommeren1, 2, K. N. Faber1, C. M. Aldaz12, R. K. Weersma1, E.A. M. Festen1, 2
1University of Groningen and University Medical Centre Groningen, Department of Gastroenterology and Hepatology, Groningen, Netherlands, 2University of Groningen and University Medical Centre Groningen, Department of Genetics, Groningen, Netherlands, 3University of Groningen and University Medical Centre Groningen, Department of Surgery, Groningen, Netherlands, 4University Medical Centre St. Radboud, Department of Gastroenterology and Hepatology, Nijmegen, Netherlands, 5Leiden University Medical Centre, Department of Gastroenterology and Hepatology, Leiden, Netherlands, 6Amsterdam Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands, 7Isala Clinics, Department of Surgery, Zwolle, Netherlands, 8University Medical Centre Utrecht, Department of Gastroenterology and Hepatology, Utrecht, Netherlands, 9University Medical Centre Maastricht, Division of Gastroenterology and Hepatology, Maastricht, Netherlands, 10VU University Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands, 11Erasmus Medical Centre, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands, 12The University of Texas M.D. Anderson Cancer Centre, Department of Molecular Carcinogenesis, Science Park, Smithville, United States
Crohn’s Disease (CD) is a chronic inflammatory disease with unpredictable disease behaviour. Insights obtained from genetic studies have advanced our understanding of the disease biology, identifying 200 genetic risk loci involved in disease development. To personalize therapeutic strategies, it is now important to identify genetic risk factors associated with disease behaviour. In the current study, we aim to identify genetic risk factors that are associated with recurrent fibrostenotic disease behaviour in CD.
To increase power to identify these disease-modifying genetic variants, we compared so-called extreme phenotypes. Severe CD was defined as patients who underwent a small bowel resection at least 2 times because of confirmed stenosis. The control group consisted of patients with mild inflammatory disease behaviour, defined as CD without any progression to stenosis, fistulae, or resection for more than 5 years. All patients were genotyped for 166 251 SNPs with the Immunochip genotyping array. Allelic association and meta-analysis were performed using PLINKv1.07 software. WWOX and TGF-β mRNA expression in ileocecal resection material from patients with and without the risk variant, as well as in intestinal tissue from Wwox knockout mice, were analysed by Q-PCR.
After a discovery phase in 242 severe CD patients and 279 CD patients with mild disease, 48 SNPs showing an allelic association with a p-value < 1E-05 were selected for follow-up with Sequenom iPlex in an independent cohort of 80 severe CD cases and 390 mild CD cases. Combined analysis revealed an intronic SNP in the WWOX gene with a genome-wide-significant association (p-value = 5E-11; OR of 3.2). Ileocecal resection tissue of CD patients carrying the risk allele showed enhanced expression of TGF-β compared with individuals homozygous for the wild-type allele. Similarly, we observed a trend towards increased TGF-β expression in the small intestine of Wwox knockout mice compared with wild-type mice.
We identified a disease-modifying gene (WWOX) associated with recurrent fibrostenotic disease behaviour in CD, which is replicated in an independent cohort. WWOX is a tumour-suppressor gene, but it also regulates inflammation through SMAD7 and TGF-β signalling. TGF-β expression is enhanced in individuals with the genetic risk variant, indicating WWOX as an important signalling modulator involved in fibrostenotic CD.