New susceptibility loci in IBD

Thursday, 10 December 2009 16:52

Research news

The search for susceptibility loci for chronique inflammatory bowel diseases (IBD)   over the last 20 years has led to identification of a number of genetic factors implicated in the pathogenesis of these diseases.

Genome-wide association studies combined with meta-analyses  constitute a   research  field  which is important for our  understanding the physiopathology of IBD, as demonstrated by two studies published in Nature Genetics1-2 in December 2009.

The first study sought to determine genes implicated in early onset of IBD.

Its hypothesis was that these particular forms, both in their clinical expression and in their severity, could reveal precise localizations of genes on the chromosomes (loci).

The authors show evidence of 5 new loci, one of them in proximity to the   IL-27 gene coding for an immunomodulating cytokine which regulates the adaptive immune response.  Analysis of  expression of IL-27 in the small intestine shows a significant decrease  in this expression in patients with early onset Crohn's disease compared to healthy controls. These results indicate that the gene may be a serious candidate.  Nevertheless, the presence of other genes in this chromosomal region point to the necessity for finer mapping and functional analyses in order to confirm the possible role of IL-27.

A certain number of genes susceptible to Crohn's disease have been identified.  Their association differs in  European and North American patients, but not  within Japanese populations.  This observation was the point of departure for the second study, which reports  the search for new susceptibility loci for UC in a Japanese population.  Three new genetic loci were thus identified.  The most significant association was observed for the FCGR2A gene coding for a receptor for IgG (FcgRIIa).  This link  of the IgGs to the receptor induces secretion of inflammatory cytokines such as TNF-a.  When this gene is associated with UC, it leads to the formation of a receptor having stronger affinity for the IgGs, thereby possibly explaining hyperactivation of the immune response observed during UC.

In conclusion, these studies of associations have led to identification of new   candidate genes with susceptibility for IBD; further studies should help to more clearly elucidate the physiopathology of these diseases.

1. Imielinski, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41, 1335-1340 (2009).

2. Asano, K. et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41, 1325-1329 (2009).