title: The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Genetic polymorphisms, in particular, the NOD2insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Tyler
authors.forename: Raquel
authors.initials: R
authors.lastname: Milgrom
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Stempak
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: John Hunter
authors.initials: JH
authors.lastname: Brumell
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.forename: Rishabh
authors.initials: R
authors.lastname: Sehgal
authors.forename: Zane
authors.initials: Z
authors.lastname: Cohen
authors.forename: Walter
authors.initials: W
authors.lastname: Koltun
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000601:surgery*; D039021:Colonic Pouches / Q000009:adverse effects*; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019449:Pouchitis / Q000209:etiology / Q000235:genetics; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein