Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation?
- S Buhner1,
- C Buning1,
- J Genschel1,
- K Kling1,
- D Herrmann1,
- A Dignass2,
- I Kuechler3,
- S Krueger1,
- H H-J Schmidt1,
- H Lochs1
- 1Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Germany
- 2Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Germany
- 3Institute of Medical Biometry, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Germany
- Correspondence to:
Dr S Bühner
Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Schumannstr 20-21, 10117 Berlin, Germany;
- Accepted 21 June 2005
- Revised 16 June 2005
- Published Online First 6 July 2005
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
Published online first 29 July 2005
Conflict of interest: None declared.