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Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation?
  1. S Buhner1,
  2. C Buning1,
  3. J Genschel1,
  4. K Kling1,
  5. D Herrmann1,
  6. A Dignass2,
  7. I Kuechler3,
  8. S Krueger1,
  9. H H-J Schmidt1,
  10. H Lochs1
  1. 1Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Germany
  2. 2Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Germany
  3. 3Institute of Medical Biometry, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Germany
  1. Correspondence to:
    Dr S Bühner
    Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Schumannstr 20-21, 10117 Berlin, Germany; sabine.buehner{at}charite.de

Abstract

Background and aim: A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn’s disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier.

Methods: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio.

Results: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability.

Conclusions: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.

  • CARD15/NOD2, capsase recruitment domain family, member 15/nucleotide binding oligomerisation domain 2
  • CD, Crohn’s disease
  • CD-R, first degree relative of a patient with CD
  • CD-NR, non-related household member living with a patient with CD
  • IBD, inflammatory bowel disease
  • LRR, C terminal leucine rich repeats
  • NFκB, nuclear transcription factor κB
  • TNF-α, tumour necrosis factor α
  • NSAID, non-steroidal anti-inflammatory drugs
  • PI, permeability index
  • WT, wild-type
  • intestinal barrier function
  • intestinal permeability
  • inflammatory bowel disease
  • CARD15/NOD2 mutation
  • gene analysis
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Footnotes

  • Published online first 29 July 2005

  • Conflict of interest: None declared.

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