PURPOSE: 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.
PURPOSE: 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 diseasepatients (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 CDpatients (n = 141) in remission. RESULTS: Our data confirm the association between JAK2rs10758669 (p = 0.026, OR = 1.25, 95% CI = 1.04-1.50) and STAT3rs744166 (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 CDpatients, an increased intestinal permeability was detected in 65 out of 141 patients (46.1%). Most importantly, patients carrying the C risk allele within JAK2rs10758669 displayed an increased permeability more often compared with patients without the C allele (p = 0.004). No association with intestinal permeability was found for STAT3rs744166 and all IRGM variants. CONCLUSIONS:JAK2rs10758669 and STAT3rs744166 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: A Dignass; G Van Assche; J O Lindsay; M Lémann; J Söderholm; J F Colombel; S Danese; A D'Hoore; M Gassull; F Gomollón; D W Hommes; P Michetti; C O'Morain; T Oresland; A Windsor; E F Stange; S P L Travis Journal: J Crohns Colitis Date: 2010-01-15 Impact factor: 9.071
Authors: M Peeters; B Geypens; D Claus; H Nevens; Y Ghoos; G Verbeke; F Baert; S Vermeire; R Vlietinck; P Rutgeerts Journal: Gastroenterology Date: 1997-09 Impact factor: 22.682
Authors: J D Söderholm; C Streutker; P-C Yang; C Paterson; P K Singh; D M McKay; P M Sherman; K Croitoru; M H Perdue Journal: Gut Date: 2004-12 Impact factor: 23.059
Authors: John D Reveille; Anne-Marie Sims; Patrick Danoy; David M Evans; Paul Leo; Jennifer J Pointon; Rui Jin; Xiaodong Zhou; Linda A Bradbury; Louise H Appleton; John C Davis; Laura Diekman; Tracey Doan; Alison Dowling; Ran Duan; Emma L Duncan; Claire Farrar; Johanna Hadler; David Harvey; Tugce Karaderi; Rebecca Mogg; Emma Pomeroy; Karena Pryce; Jacqueline Taylor; Laurie Savage; Panos Deloukas; Vasudev Kumanduri; Leena Peltonen; Sue M Ring; Pamela Whittaker; Evgeny Glazov; Gethin P Thomas; Walter P Maksymowych; Robert D Inman; Michael M Ward; Millicent A Stone; Michael H Weisman; B Paul Wordsworth; Matthew A Brown Journal: Nat Genet Date: 2010-01-10 Impact factor: 38.330