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.
Buhner
S
S
Department of Gastroenterology, Hepatology, and Endocrinology, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Schumannstr 20-21, 10117 Berlin, Germany. sabine.buehner@charite.de
Buning
C
C
Genschel
J
J
Kling
K
K
Herrmann
D
D
Dignass
A
A
Kuechler
I
I
Krueger
S
S
Schmidt
H H-J
HH
Lochs
H
H
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