title: The JAK2 variant rs10758669 in Crohn's disease: altering the intestinal barrier as one mechanism of action.
abstract: OBJECTIVE
  The aetiology of intestinal barrier dysfunction in Crohn's disease (CD) is poorly understood. Associations in relatives of CD families suggest a genetic basis, but the relevant variants are still unknown. We hypothesized that variants in genes occurring in pathways such as autophagy and IL23 signalling might contribute to CD by altering intestinal permeability.
  
  
  METHODS
  We analysed five variants (rs10758669 within JAK2, rs744166 within STAT3, rs4958847, rs11747270 and rs13361189 within IRGM) in adult German inflammatory bowel disease patients (CD, n = 464; ulcerative colitis (UC), n = 292) and matched healthy controls (n = 508). These data were correlated with gastrointestinal permeability as assessed by lactulose/mannitol ratio in CD patients (n = 141) in remission.
  
  
  RESULTS
  Our data confirm the association between JAK2 rs10758669 (p = 0.026, OR = 1.25, 95% CI = 1.04-1.50) and STAT3 rs744166 (p = 0.04, OR = 0.83, 95% CI = 0.688-0.998) with CD, but not UC. With respect to all the analysed IRGM variants, no association was found to either CD or UC. Among CD patients, an increased intestinal permeability was detected in 65 out of 141 patients (46.1%). Most importantly, patients carrying the C risk allele within JAK2 rs10758669 displayed an increased permeability more often compared with patients without the C allele (p = 0.004). No association with intestinal permeability was found for STAT3 rs744166 and all IRGM variants.
  
  
  CONCLUSIONS
  JAK2 rs10758669 and STAT3 rs744166 increase susceptibility for CD. We show that the A>C substitution in rs10758669 of the JAK2 gene is associated with increased intestinal permeability. Altering intestinal barrier function might thus be one mechanism how JAK2 contributes to CD pathogenesis.
authors: Department of Medicine, Division of Gastroenterology, Infectiology and Rheumatology, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, Berlin 10117, Germany.
authors: Matthias
authors: M
authors: Prager
authors: Janine
authors: J
authors: Büttner
authors: Verena
authors: V
authors: Haas
authors: Daniel C
authors: DC
authors: Baumgart
authors: Andreas
authors: A
authors: Sturm
authors: Martin
authors: M
authors: Zeitz
authors: Carsten
authors: C
authors: Büning
mesh_terms: D000328:Adult; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000209:etiology / Q000235:genetics*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010539:Permeability; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D053473:Nod2 Signaling Adaptor Protein; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019204:GTP-Binding Proteins; C513539:IRGM protein, human