Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?

Gut. 2006 Mar;55(3):342-7. doi: 10.1136/gut.2005.065557. Epub 2005 Jul 6.

Abstract

Background and aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Crohn Disease / genetics*
  • Crohn Disease / physiopathology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Intestinal Absorption / genetics*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Male
  • Middle Aged
  • Mutation*
  • Nod2 Signaling Adaptor Protein
  • Permeability
  • Polymorphism, Genetic

Substances

  • Intracellular Signaling Peptides and Proteins
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein