CROHN'S DISEASE - ASSOCIATED NOD2 VARIANTS SHARE A SIGNALING DEFECT IN
RESPONSE TO LIPOPOLYSACCHARIDE AND PEPTIDOOGLYCAN

Background & Aims: The NOD2 variants R702W, G908R, and L1007fsinsC are
strongly associated with Crohn's disease (CD) in both European and American
populations, but whether this susceptibility extends to all ethnic groups
remains unknown. Except for the L1007fsinsC mutation, which produces a
truncated NOD2 protein, the functional activity of the major CD-associated
variants G908R and R702W is unknown.

Methods: Individuals were genotyped for R702W, G908R, and L1007fsinsC. The
ability of G908R, R702W, and L1007fsinsC variants in the presence and
absence of P268S to confer responsiveness to lipopolysaccharide (LPS) and
peptidoglycan (PGN) was determined in HEK293T kidney cells.

Results: G908R and L1007fsinsC, but not R702W, were associated with disease
susceptibility in Ashkenazi Jews. Ashkenazi Jews with CD had significantly
higher allele frequency carriage of G908R and lower carriage of R702W
compared with non-Jewish whites with CD. Functional studies revealed that
the G908R, R702W, and L1007fsinsC variants in the presence and absence of
P268S are defective in their ability to respond to bacterial LPS and PGN,
whereas P268S alone exhibited wild-type activity.

Conclusions: R702W is not associated with susceptibility to CD in Ashkenazi
Jews. The G908R, R702W, and L1007fsinsC variants share a common signaling defect
in response to bacterial components, providing evidence for a unifying molecular
mechanism whereby NOD2 mutations contribute to disease susceptibility.