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The JAK2 variant rs10758669 in Crohn’s disease: altering the intestinal barrier as one mechanism of action

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

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.

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Acknowledgement

The study was supported by a grant from the Eli and Edythe Broad Foundation (to C.B., Proposal No. IBD-0164R), by a grant of the German Ministry for Education and Research (BMBF)—Competence Network “Inflammatory Bowel Disease”: 01GI0284 TP 1.17 and by the Forschungsförderung of the Charité, Universitätsmedizin Berlin. We thank all patients who participated in this evaluation.

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Authors and Affiliations

  1. Department of Medicine, Division of Gastroenterology, Infectiology and Rheumatology, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, Berlin, 10117, Germany

    Matthias Prager, Janine Büttner, Martin Zeitz & Carsten Büning

  2. Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany

    Verena Haas

  3. Department of Medicine, Division of Hepatology and Gastroenterology, Charité, Universitätsmedizin Berlin, Campus Virchow, Augsutenburger Platz 1, Berlin, 1335, Germany

    Daniel C. Baumgart & Andreas Sturm

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  1. Matthias Prager
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Correspondence to Carsten Büning.

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Prager, M., Büttner, J., Haas, V. et al. The JAK2 variant rs10758669 in Crohn’s disease: altering the intestinal barrier as one mechanism of action. Int J Colorectal Dis 27, 565–573 (2012). https://doi.org/10.1007/s00384-011-1345-y

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  • DOI: https://doi.org/10.1007/s00384-011-1345-y

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