title: Genetic risk profiling and gene signature modeling to predict risk of complications after IPAA.
abstract: BACKGROUND
  Severe pouchitis and Crohn's disease-like complications are 2 adverse postoperative complications that confound the success of the IPAA in patients with ulcerative colitis. To date, approximately 83 single nucleotide polymorphisms within 55 genes have been associated with IBD.
  
  
  OBJECTIVE
  The aim of this study was to identify single-nucleotide polymorphisms that correlate with complications after IPAA that could be utilized in a gene signature fashion to predict postoperative complications and aid in preoperative surgical decision making.
  
  
  METHODS
  One hundred forty-two IPAA patients were retrospectively classified as "asymptomatic" (n = 104, defined as no Crohn's disease-like complications or severe pouchitis for at least 2 years after IPAA) and compared with a "severe pouchitis" group (n = 12, ≥ 4 episodes pouchitis per year for 2 years including the need for long-term therapy to maintain remission) and a "Crohn's disease-like" group (n = 26, presence of fistulae, pouch inlet stricture, proximal small-bowel disease, or pouch granulomata, occurring at least 6 months after surgery). Genotyping for 83 single-nucleotide polymorphisms previously associated with Crohn's disease and/or ulcerative colitis was performed on a customized Illumina genotyping platform. The top 2 single-nucleotide polymorphisms statistically identified as being independently associated with each of Crohn's disease-like and severe pouchitis were used in a multivariate logistic regression model. These single-nucleotide polymorphisms were then used to create probability equations to predict overall chance of a positive or negative outcome for that complication.
  
  
  RESULTS
  The top 2 single-nucleotide polymorphisms for Crohn's disease-like complications were in the 10q21 locus and the gene for PTGER4 (p = 0.006 and 0.007), whereas for severe pouchitis it was NOD2 and TNFSF15 (p = 0.003 and 0.011). Probability equations suggested that the risk of these 2 complications greatly increased with increasing number of risk alleles, going as high as 92% for severe pouchitis and 65% for Crohn's disease-like complications.
  
  
  CONCLUSIONS
  In this IPAA patient cohort, mutations in the 10q21 locus and the PTGER4 gene were associated with Crohn's disease-like complications, whereas mutations in NOD2 and TNFSF15 correlated with severe pouchitis. Preoperative genetic analysis and use of such gene signatures hold promise for improved preoperative surgical patient selection to minimize these IPAA complications.
authors.affiliation: Division of Colon and Rectal Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850, USA. rishsehgal@gmail.com
authors.forename: Rishabh
authors.initials: R
authors.lastname: Sehgal
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Polinski
authors.forename: John P
authors.initials: JP
authors.lastname: Hegarty
authors.forename: Zhenwu
authors.initials: Z
authors.lastname: Lin
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McKenna
authors.forename: David B
authors.initials: DB
authors.lastname: Stewart
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Poritz
authors.forename: Walter A
authors.initials: WA
authors.lastname: Koltun
mesh_terms: D003092:Colitis / Q000235:genetics; D003093:Colitis, Ulcerative / Q000235:genetics*; D039021:Colonic Pouches / Q000009:adverse effects*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D019449:Pouchitis / Q000235:genetics*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics; D012306:Risk; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C545650:PTGER4 protein, human; D058309:Receptors, Prostaglandin E, EP4 Subtype; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15