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The Genetic Component of Crohn's Disease

Several genes have been implicated in the etiology of Crohns Disease, the most prominent of which are the NOD2/CARD15 located on chromosome 16,27,28 the OCTN1 gene located on chromosome 5,29,30 and the DLG5 gene located on chromosome 10.31 The exact mechanism responsible for NOD2/ CARD15's role in the intestinal immune response remains unclear, but mutations of the gene and resultant changes in its function may disrupt the intestinal mucosal barrier and the immune response to the bacterial milieu in the gut.27,32,33 A recent study of 205 patients with diagnosed Crohn's Disease from northwestern France and 95 ethnically matched healthy controls revealed the R702 mutation of the NOD2 gene demonstrated a significant association with Crohns Disease and was independently associated with stricturing activity.34 In a study of 512 German and British Crohns DIsease patients, an insertion polymorphism in NOD2 conferred a significantly increased susceptibility to Crohns Disease in these patients.28

The DLG5 gene has a lesser but significant impact on the risk for developing Crohn's Disease. Although the exact mechanism responsible has not been determined, DLG5 encodes a scaffolding protein important for maintaining epithelial integrity in various organs.31 DLG5 may interact additively with the NOD2/CARD15 gene to increase susceptibility to Crohn's Disease. Gene OCTN1 is located on chromosome 5q31, codes for an ion channel, and also has a lesser impact on Crohn's Disease risk than NOD2/ CARD15.35 Mutations in this gene may disrupt ion channels via altered function of cation transporters and cell-to-cell signaling in the intestinal epithelium in Crohns patients.30

The TLR4 gene has recently been implicated in Crohns Disease but is not associated with the chromosomal region previously linked to Crohn Disease. TLR4 codes for lipopolysaccharide (LPS) signaling, bacterial recognition, and subsequent immune response to bacterial insult. In Crohns patients, the TLR4 gene is expressed in intestinal epithelial cells, macrophages, and dendritic cells of inflamed intestinal mucosa. Disruption of the LPS signaling pathway could result in an altered immune response to pathogens and a subsequent increase of intestinal inflammation. In two cohorts of 448 Belgian patients diagnosed with Crohn Disease (n=334, n=114) and 140 controls, it was demonstrated TLR4 polymorphisms enhance the relative risk of developing Crohns Disease compared to controls. It was also found that polymorphisms of both TLR4 and NOD2 increased this risk.36 In 2001, a group of Hungarian researchers identified a genetic marker for IBD, the Leiden point mutation, and concluded the prevalence of this mutation was significantly increased in 49 Crohns Disease patients compared to 57 healthy controls (27.6% versus 5.3%), specifically in central European patients compared to southern or northern European or American patients.37,38


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