title: Mutation in TAGAP is protective of anal sepsis in ileocolic Crohn's disease.
abstract: BACKGROUND
  Anal complications of Crohn's disease range from painless skin tags to debilitating fistulas that are imperfectly treated with tumor necrosis factor antagonists. The recent discovery of more than 190 single-nucleotide polymorphisms associated with Crohn's disease offers the opportunity to genetically define the severity of anal disease in Crohn's disease and possibly predict prognosis and anti-tumor necrosis factor response.
  
  
  OBJECTIVE
  This study aimed to identify single nucleotide polymorphisms associated with anal disease generally, septic anal disease specifically and the responsivity to anti-tumor necrosis factor treatment.
  
  
  METHODS
  All patients with ileocolonic Crohn's disease were identified from our IBD registry. One hundred ninety-six Crohn's disease-related single-nucleotide polymorphisms were analyzed by the use of a custom microarray chip. Patients' response to anti-tumor necrosis factor treatment was then assessed.
  
  
  RESULTS
  One hundred sixteen patients with ileocolonic Crohn's disease were identified and assigned to septic anal disease (abscesses/fistulas, n = 35), benign anal disease (skin tags/fissures/isolated pain, n = 17), and no anal disease (n = 64) cohorts. Single-nucleotide polymorphism rs212388 negatively correlated with the presence of anal disease overall and septic disease specifically. The presence of the non-wild-type allele 'G' was protective of anal sepsis with homo- and heterozygotes having a 75% chance of no anal disease (p = 0.0001). The homozygous wild-type group had the highest risk of septic disease and included 3 of 4 patients requiring diverting ileostomies. Twenty-four patients were treated with anti-tumor necrosis factors. Nine had a beneficial response (assessed at >6 months); however, no single-nucleotide polymorphism correlated with anti-tumor necrosis factor response. Rs212388 is associated with the TAGAP molecule involved in T-cell activation.
  
  
  CONCLUSIONS
  Rs212388 most significantly correlated with the presence and severity of anal disease in ileocolonic Crohn's disease. A single copy of the risk allele was protective, whereas wild-type homozygotes had the highest risk of septic disease and stoma creation. In this select group, no single-nucleotide polymorphism was predictive of anti-tumor necrosis factor response. Mutations in TAGAP may predict a more benign form and course of anal disease in Crohn's disease.
authors.affiliation: Division of Colon and Rectal Surgery, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Connelly
authors.forename: Rishabh
authors.initials: R
authors.lastname: Sehgal
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Berg
authors.forename: John P
authors.initials: JP
authors.lastname: Hegarty
authors.forename: Sue
authors.initials: S
authors.lastname: Deiling
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: D000038:Abscess / Q000188:drug therapy / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001004:Anus Diseases / Q000235:genetics*; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000235:genetics; D003424:Crohn Disease / Q000150:complications* / Q000235:genetics*; D005260:Female; D005401:Fissure in Ano / Q000188:drug therapy / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012003:Rectal Fistula / Q000188:drug therapy / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D020690:GTPase-Activating Proteins; C557017:TAGAP protein, human; D014409:Tumor Necrosis Factor-alpha