Positional cloning of IBD genes

Using a positional cloning approach, several investigators were able to detect linkage to IBD on different chromosomes (Cho et al., 1998; Duerr et al., 2000; Hampe et al., 1999a; Hampe et al., 1999b; Hugot et al., 1996; Rioux et al., 2000; Satsangi et al., 1996b). Nine IBD loci are today accepted as firmly established according to the criteria defined by Kruglyak and Lander (Figure 20.1). Additional loci exhibit suggestive evidence of linkage. Finally, a meta-analysis of the published genome scans revealed a significant linkage in the HLA region and suggestive linkage on the previously reported regions 5q, 7q and 16 and on three additional regions: 2q (IBD), 3q (CD) and 17q (CD) (van Heel et al., 2004). Among all the reported loci, not one has an attributable Is value higher than 2, indicating that IBD are complex genetic traits with no major gene. Most of the loci (all but IBD2) seem to be involved in CD. In contrast, several loci do not seem to play a significant role in UC (IBD1, 4, 5 and DGL5), arguing again in favour of a stronger genetic component for CD than for UC. Finally, among the nine IBD loci, three genes involved in CD predisposition have been identified using a positional cloning approach: CARD15, SLC22A4/5 and DLG5 (see below).

On chromosome 5, the IBD5 locus was localized to a region of 250 kb within an area containing several cytokine genes (Rioux et al., 2000; 2001). In fact, the identified genes (SLC22A4 and SLC22A5) do not code for cytokines but for the organic cation transporters OCTN1 and OCTN2 respectively (Peltekova et al., 2004). Two genetic variants in strong linkage disequilibrium with each other have been associated with CD. The haplotype defined by these two variants is present in 42% of healthy controls and 54% of CD patients. The associated protein seems to interact with CARD15/NOD2. The first genetic variant codes for a non-conservative amino acid substitution (L503F) in the OCTN1 protein. This variant alters the Vmax and Km constants of the transporter toward several substrates, including carnitine and xenobiotics. The second genetic variant (-207G>C) affects a heat shock transcription factor element in the promoter of SLC22A5 resulting in decreased transcription of the gene when activated. The two genes are widely expressed but their function in the context of IBD remains highly speculative. However, it should be noted that a genetic polymorphism located in a promoter RUNX1 element of SLC22A4 has been associated with rheumatoid arthritis, providing a link between these two inflammatory disorders (Tokuhiro et al., 2003). As a result, the OCTN genes may have an unexpected but important role in immune disorders.

A gene on chromosomal band 10q23 has also been identified recently (Stoll et al., 2004). Two main variants within the DLG5 gene coding for non-conservative substitutions of the protein (R30Q and P1371Q) have been associated with CD and possibly with UC. The first mutation is relatively frequent in the general population (34%) while the second one is rare (less than 1%). This observation was made using case-control and transmission disequilibrium analyses in several independent White populations, together with reports of additional private variants. An interaction with CARD15/NOD2 is likely. DLG5 encodes a

Genes With Ibd

Figure 20.1 Localization of the IBD loci. Three genes (in red) playing a role in CD have been identified by a positional cloning approach: CARD15/NOD2, SLC22A4/5 and DLG5. 6 loci (in green) have shown significant linkage while other loci have only demonstrated suggestive linkage in single genome-scan analyses (in blue) or in the meta-analysis of the reported genome-scans (in pink).

Figure 20.1 Localization of the IBD loci. Three genes (in red) playing a role in CD have been identified by a positional cloning approach: CARD15/NOD2, SLC22A4/5 and DLG5. 6 loci (in green) have shown significant linkage while other loci have only demonstrated suggestive linkage in single genome-scan analyses (in blue) or in the meta-analysis of the reported genome-scans (in pink).

scaffolding protein that may be important for the maintenance of epithelial integrity. It contains several PDZ domains. Here too, the functional link between this gene and the IBD phenotype remains to be explored. In fact, the discoveries of DLG5 and the genes coding for the OCTN transporters demonstrate the power of positional cloning approach in IBD: these genes would certainly not have been investigated as candidate genes on the basis of their known functions.

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