About 70% of patients with primary sclerosing cholangitis (P.S.C.) also have inflammatory bowel disease (I.B.D.); mostly ulcerative colitis (U.C.), and sometimes Crohn's disease. Because of this relationship between I.B.D. and P.S.C. it is important to consider the factors that may contribute to I.B.D. -- this may provide clues to the causes of P.S.C. A large number of studies have shown that heritable factors (i.e. genes) are of central importance in determining predisposition to I.B.D. This article is the first in a series which will discuss the complex genetic basis of I.B.D.

There has been rapid progress in identifying I.B.D. susceptibility genes in the last few years. The first I.B.D. gene to be identified was the NOD2/CARD15 gene (gene map locus 16q12) associated with Crohn's disease, and so it seems appropriate to begin this article with a discussion of this gene which has been the most intensively investigated.

CARD stands for "Caspase recruitment domain-containing protein". NOD stands for "nucleotide-binding oligomerization domain". The NOD2/CARD15 protein encoded by the NOD2/CARD15 gene is thought to be an intracellular receptor for bacterial products that controls signals that lead to activation/inactivation of nuclear factor-kappa B (NFKB). NFKB activation in turn activates tumor necrosis factor alpha (TNFa) which then activates the inflammation response.

Recent studies indicate that the normal NOD2/CARD15 protein senses muramyl dipeptide derived from peptidoglycans of bacterial cell walls. Normally, when activated by muramyl dipeptide, the NOD2/CARD15 protein inhibits the signalling from a receptor, Toll-like receptor 2 (TR2), to NFKB. But when the NOD2/CARD15 gene is mutated the NOD2/CARD15 protein is unable to sense muramyl dipeptide and prevent Toll-like receptor 2 from signalling to NFKB. TNFa is therefore switched on, and consequently there is uncontrolled inflammation, resulting in Crohn's disease:

TLR2 ---> ---> NFKB ---> TNFa ---> Inflammation

These discoveries are important because they define how a change in the signalling pathway by which bacterial products are sensed in the gut can lead to inflammation. This has provided several clues as to other genes that may regulate inflammation in inflammatory bowel disease.

A recently identified gene determining susceptibility to Crohn's disease is the gene NFKBIA (nuclear factor of kappa light chain gene enhancer in B cells inhibitor, alpha) (gene map locus 14q13). The protein encoded by this gene normally downregulates the activity of NFKB. Mutation in the NFKBIA gene produces an effect similar to the NOD2/CARD15 mutation; that is, uncontrolled activation of NFKB, uncontrolled TNFa activation, and inflammation. Not surprisingly, certain mutations (polymorphisms) in the TNFa gene (gene map locus 6p21.3) may also contribute to IBD. Moreover, polymorphisms in the promoter region of NFKB1 (the gene encoding NFKB) (gene map locus 4q23-q24) are associated with risk of ulcerative colitis.

While Toll-like receptor 2 (TLR2) senses peptidoglycans of bacterial cell walls, Toll-like receptor 4 (TLR4) senses lipopolysaccharides excreted by Gram-negative bacteria. Like TLR2, TLR4 activation sends signals that ultimately lead to activation of NFKB and TNFa. Mutations or polymorphisms in the TLR4 gene (gene map locus 9q32-q33) have recently been shown to be associated with both Crohn's disease and ulcerative colitis:

TLR4 ---> ---> NFKB ---> TNFa ---> Inflammation

These discoveries have come hand-in-hand with the development of new biological therapies for controlling inflammation in Crohn's disease and other inflammatory disease. The most important of these has been the development of TNFa antibodies/inhibitors such as Remicade (infliximab) and Enbrel (etanercept).

Additional genes contributing to Crohn's disease and ulcerative colitis will be discussed in subsequent articles in this series.

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