Association of NOD2/CARD15 With Crohn Disease
In early 2001, two groups independently published back-to-back articles in Nature identifying the gene NOD2 (also called CARD15) as the first susceptibility gene for Crohn disease (CD). [1, 2] Three mutations within the leucine-rich repeat region were associated with CD (see the image below), and these and other studies have demonstrated an approximately 2-fold risk for CD in NOD2 heterozygotes and an approximately 20-fold risk for CD in NOD2 homozygotes or complex heterozygotes. [3, 4, 5, 6, 7, 8]
Additional evidence of the contribution of NOD2 in CD was demonstrated by a study in which the NOD2 gene was sequenced and additional, rare polymorphisms that increase the risk of the development of CD were identified. 
NOD2 was identified as an intracellular protein in the proinflammatory nuclear factor kappa B (NFkB) pathway, and the leucine-rich repeat was identified as a receptor for bacterial products (now known to be muramyl dipeptide). In one of these studies, cells transfected with one of the “mutant” forms of NOD2 demonstrated decreased NFkB activity in response to stimulation by a number of common bacteria. 
The identification of this genetic association was highly significant for researchers, as it not only proved that genes for genetically complex diseases such as CD could actually be identified (the NOD2/CD finding was, arguably, the first major success in genetically complex diseases), but it also supported the long-held hypothesis that CD was a heritable condition in which affected individuals had an abnormal response to “friendly” bacteria.
How the 3 associated NOD2 variants increase susceptibility to CD remains the subject of considerable debate. One of the index association studies suggests that the mutations have a “loss of function” effect, meaning that after bacterial stimulation, there was reduced NFkB expression. Yet this finding was counterintuitive, as CD is a disease characterized in part by elevated NFkB levels.
One possible explanation was that this “defect” in the innate immune system allows intracellular bacteria to escape the first-line defense of the immune system, thereby leading to an enhanced adaptive response. Other groups have suggested that, under normal circumstances, NOD2 acts as a negative regulator following bacterial stimulation of the cell surface receptor toll-like receptor-2, and that the CD-associated mutations result in a loss of this “brake” on the immune response leading to elevated NFkB. 
A further theory suggests that NOD2 mutations lead to a reduction in the production of alpha-defensins (small antibacterial proteins) by Paneth cells located in the small bowel.  To date, however, no single theory as to how NOD2 increases susceptibility to CD has been accepted. Of note, no role for NOD2 has been demonstrated in ulcerative colitis.
More recent work has suggested that NOD2 may have some role in autophagy, a process that, among other things, deals with intracellular “debris,” including bacterial products.  This finding is of particular interest because other known CD genes play significant roles within the autophagy pathways and highlights an evolving phenomenon; although the number of CD-associated genes increases (currently >70 susceptibility loci), many of the new genes fall into pathways already identified as important in the development of chronic GI inflammation. 
More information about Crohn disease and NOD2/CARD15 can be found in the main article on Crohn Disease.
Possible Clinical Role of NOD2/CARD15 in Crohn Disease
The identification of NOD2 raised the prospect of its potential role in clinical practice. Could NOD2 be used as part of the diagnostic workup for suspected cases of Crohn disease (CD)? Unfortunately not, as the vast majority of people who carry NOD2 mutations or are even homozygotes for NOD2 mutations will not develop CD. This is true of all known genetic variants associated with inflammatory bowel disease and there is no role for genetic testing in CD at this point in time.
Nevertheless, the question has been raised as to whether there might be some benefit to knowing NOD2 status. NOD2 mutations are associated with small bowel CD and, in some studies, with stricturing disease.  This anatomical association negates the use of NOD2 in distinguishing CD from ulcerative colitis, as further diagnostic tests are not needed to distinguish small bowel from colonic inflammation.
Parameters that helped distinguish Crohn colitis from ulcerative colitis would, however, be extremely useful on certain occasions, such as when patients were being considered for colectomy. Specifically, CD patients who carry NOD2 mutations are more likely to require small bowel surgery, and there is evidence of a gene-dose effect: NOD2 homozygotes, on average, require surgery sooner than do heterozygotes, who, in turn, require surgery earlier than do wild-type homozygotes.
However, this effect is not strong enough alone to influence clinical practice. It may be that a combination of genetic profiles is needed to have a sufficiently large effect, but further work is needed in additional cohorts.  One study has suggested an additive effect of NOD2 variation and IBD-related serologies and the development of more severe CD; however, this finding requires validation. 
Studies have also been unable to consistently demonstrate any association between NOD2 variants and an ability to predict response to any of the CD therapeutic approaches such as thiopurines or anti–tumor necrosis factor therapies. Furthermore, the NOD2 pathway is not readily amenable to therapeutic intervention.
Although the discovery of NOD2 has not yet led to any direct clinical benefits, it has paved the way for additional genetic discoveries, such as the associations between CD and the interleukin-23 receptor pathway that may yet lead directly to clinical benefits through the development of compounds designed to interact with this pathway. There can be little doubt that the huge strides in our understanding of the genetic background of CD, stimulated by the NOD2 discovery, will, in the future, have a direct influence on how clinicians deliver care.