Lessons to be learned from the NOD2 gene in Crohn's disease

The recent discovery that CARD15/NOD2 is involved in the genetic predisposition to Crohn's disease (CD) provides the final demonstration that CD is a genetic disorder. The gene explains about 20% of the genetic susceptibility. CARD15 mutations are present in 30-50% of CD patients compared to 7-20% of healthy controls. Interestingly, CD patients often carry mutations on their two chromosomes suggesting a mutation dose effect. Unfortunately, even if the association between the three main CARD15 mutations (R702W, G908R and 1007fs) and CD is clearly established, it is not useful today to genotype asymptomatic at risk people or inflammatory bowel disease patients as a routine. More interestingly and for the first time, CARD15 points out a specific pathway involved in CD mechanism. Because CARD15 is able to be activated by components of the bacterial wall and further induce the activation of NFkappaB, a proinflammatory molecule, CARD15 discovery makes the link, at the molecular level, between bacteria and inflammation of the digestive tract.