Over the past 15 years, a wide variety of candidate genes have been studied. Most associations identified between specific candidate genes, including major-histocompatibility-complex loci, and inflammatory bowel disease have not been reproducible, have not shed new light on pathogenesis, or have not facilitated diagnosis
1 . However, substantial progress has now been made with the use of the less biased approach of genome-wide screening with microsatellite DNA markers. Detailed mapping of chromosome 16 has recently resulted in the identification of a gene responsible, at least in part, for this linkage
2 . This gene encodes a cytoplasm protein designated NOD2 (also referred to as CARD 15 [caspase activation and recruitment domain]), which is expressed in macrophages and may serve as a so-called pattern-recognition receptor for bacterial lipopolysaccharide, perhaps regulating nuclear factor-κB(NF-κB) activation and macrophage apoptosis. European and North American patients with Crohn’s disease, including those without a family history of inflammatory bowel disease, are more likely to have variants of NOD2 than are persons without Crohn’s disease. Paradoxically, these NOD2 variants appear to result in reduced macrophage activation of nuclear factor- B in response to lipopolysaccharide. Persons who are homozygous for variant NOD2 may have a 20-fold or more increase in susceptibility to Crohn’s disease, with a particular predilection for ileal disease
3 . Heterozygotes are also at increased risk. However, fewer than 20 percent of patients with Crohn’s disease are homozygous for these NOD2 variants. A putative locus associated with early-onset Crohn’s disease appears to be present on chromosome 5 in the vicinity of genes encoding a variety of cytokine receptors.
Read More: Pathogenesis of inflammatory bowel disease