Update on genetics of inflammatory bowel disease

Complex genetic disorders such as inflammatory bowel disease (IBD) result from the interplay between multiple genetic and environmental risk factors. The recent identification of variants of the CARD15/NOD2 protein as contributing to Crohn disease represents a major advance in defining disease pathogenesis. CARD15/NOD2 is expressed in monocytes and is capable of activating nuclear factor kappa B (NF-kappaB). Crohn disease-associated mutations in CARD15/NOD2 predominate in its C-terminus leucine-rich repeat domain, which is required for bacterial lipopolysaccharide-dependent induction of NF-kappaB activity. The relative risk of developing Crohn disease is estimated to be in the range of 2 to 3 in people carrying one mutation and 20 to 40 in people carrying two mutations in CARD15/NOD2. Homozygote and compound heterozygote carriers of CARD15/NOD2 mutations are characterized by an earlier age of onset, less involvement of the left colon, and positive association with stricturing disease. However, even carriers of two CARD15/NOD2 mutations have limited disease penetrance (ie, only a minority will develop the disease), suggesting that additional interacting genes and environmental triggers are required for disease expression. Several additional genetic regions have been implicated through genetic linkage and association studies.