Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.
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.
Chamaillard
Mathias
M
Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, 27 Rue Juliette Dodu, 75010 Paris, France.
Philpott
Dana
D
Girardin
Stephen E
SE
Zouali
Habib
H
Lesage
Suzanne
S
Chareyre
Fabrice
F
Bui
The Hung
TH
Giovannini
Marco
M
Zaehringer
Ulrich
U
Penard-Lacronique
Virginie
V
Sansonetti
Philippe J
PJ
Hugot
Jean-Pierre
JP
Thomas
Gilles
G
D000483:Alleles; D001419:Bacteria / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D003424:Crohn Disease / Q000209:etiology* / Q000235:genetics* / Q000382:microbiology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan / Q000378:metabolism; D010641:Phenotype
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan