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The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis
  1. Andrea D Tyler1,2,
  2. Raquel Milgrom2,
  3. Joanne M Stempak2,
  4. Wei Xu3,
  5. John Hunter Brumell1,4,5,
  6. Aleixo M Muise1,4,6,
  7. Rishabh Sehgal7,
  8. Zane Cohen1,2,
  9. Walter Koltun7,8,
  10. Bo Shen9,
  11. Mark S Silverberg1,2
  1. 1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  2. 2Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, Ontario, Canada
  3. 3Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
  4. 4Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
  5. 5Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  6. 6Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
  7. 7Division of Colon and Rectal Surgery, Department of Surgery, Penn State Milton S Hershey Medical Center, Hershey, Pennsylvania, USA
  8. 8Department of Cellular and Molecular Physiology, Penn State Milton S Hershey Medical Center, Hershey, Pennsylvania, USA
  9. 9Center for Inflammatory Bowel Disease, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
  1. Correspondence to Dr Mark S Silverberg, Mount Sinai Hospital, 600 University Ave, Room 441, Toronto, ON M5G 1X5, Canada; msilverberg{at}


Background Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common.

Objective To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn's disease-like (CDL) phenotype.

Design 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype.

Results Clinical and genetic data were available on 714 individuals. 487 (68.2%) were classified as NCP, 118 (16.5%) CP and 109 (15.3%) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The NOD2insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10−5). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in NOX3 (rs6557421, rs12661812), DAGLB (rs836518) and NCF4 (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-Saccharomyces cerevisiae antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10−7) for NCP versus CP/CDL and 3.22 (p=4.11×10−8) for NCP versus CDL, respectively.

Conclusion Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.

  • Ileal pouch-anal anastomosis
  • NOD2
  • inflammatory bowel disease genetics
  • restorative proctocolectomy
  • ulcerative colitis

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  • Funding This study was supported by a grant from the Crohn's and Colitis Foundation of Canada. MSS is partially supported by the Gale and Graham Wright Research Chair in Digestive Disease. Partial funding for genotyping was supported by a CIHR operating grant (MOP97756) to AMM and JHB.

  • Competing interests MSS receives speaker fees, consulting fees and research support from Prometheus Laboratories.

  • Ethics approval Research ethics boards of Mount Sinai Hospital, Cleveland Clinic and Milton S Hershey Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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