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Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3455-60. Epub 2003 Mar 7.

Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.

Author information

1
Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, 27 Rue Juliette Dodu, 75010 Paris, France.

Abstract

CARD15 is a major susceptibility gene for a frequent multifactorial chronic inflammatory bowel disorder, Crohn disease (CD). By using NF-kappaB activation assays, the cytosolic CARD15 was shown to efficiently detect bacterial peptidoglycan (PGN), reminiscent of the PGN recognition protein surveillance mechanism in Drosophila. The 3 CD-associated variants and 13 additional variants carried by CD patients demonstrated impaired PGN-dependent response revealing null, hypomorphic, or dominant-negative properties. Quantitative parametrization of this response, computed from the patients' CARD15 genotypes, was predictive of several variable CD manifestations. In contrast, CARD15 alleles associated with Blau's syndrome promoted PGN-independent NF-kappaB activation, an observation that accounts for the minimal microbial input in the etiology of this dominant, monogenic inflammatory disorder affecting solely aseptic sites.

PMID:
12626759
PMCID:
PMC152314
DOI:
10.1073/pnas.0530276100
[Indexed for MEDLINE]
Free PMC Article

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