Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases

Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3455-60. doi: 10.1073/pnas.0530276100. Epub 2003 Mar 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Bacteria / genetics
  • Bacteria / immunology
  • Bacteria / pathogenicity
  • Carrier Proteins / genetics*
  • Cell Line
  • Crohn Disease / etiology*
  • Crohn Disease / genetics*
  • Crohn Disease / microbiology
  • Genetic Variation
  • Genotype
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Lipopolysaccharides / metabolism
  • NF-kappa B / metabolism
  • Nod2 Signaling Adaptor Protein
  • Peptidoglycan / metabolism
  • Phenotype

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Peptidoglycan