Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?
OBJECTIVE
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.
Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Schumannstr 20-21, 10117 Berlin, Germany. sabine.buehner@charite.de
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S
Buhner
C
C
Buning
J
J
Genschel
K
K
Kling
D
D
Herrmann
A
A
Dignass
I
I
Kuechler
S
S
Krueger
H H-J
HH
Schmidt
H
H
Lochs
D000293:Adolescent; D000328:Adult; D000368:Aged; D003424:Crohn Disease / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D010539:Permeability; D011110:Polymorphism, Genetic
D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein