Latest genome-wide association study throws up targets for Crohn’s and IBD

Research lead

Two of the largest-ever studies of the genetics of inflammatory bowel disease (IBD) – one looking at ulcerative colitis, the other at childhood-onset inflammatory bowel disease – have identified key genetic regions that increase susceptibility to these conditions.

The ulcerative colitis study shows the first conclusive evidence of the role played by genetic defects in the epithelium, the layer of cells which line the gut.

To date seven genes have been identified as involved in these diseases. Now, two studies completed with funding from the UK’s Wellcome Trust with support from the National Association for Colitis and Crohn’s Disease have identified a further three genetic regions that affect susceptibility to ulcerative colitis and five which relate to childhood IBD.

Researchers from the UK IBD Genetics Consortium and the Wellcome Trust Case Control Consortium scanned the genomes and followed up promising signals in a total of almost 4,700 patients affected by ulcerative colitis and compared the results with over 8000 controls. All were UK residents of European ancestry. This is over twice as large as previous scans, allowing far greater robustness.

The scans highlighted genetic variants in three regions of the genome which appear to increase the risk of ulcerative colitis. These were found on chromosomes seven, sixteen and twenty and each contains at least one biologically-relevant candidate gene. All of the candidate genes – LAMB1, CDH1, CDH3 and HNF4A – are known to play a role in creating, repairing and managing the function of the epithelium, which lines the intestine and acts as a barrier between gut bacteria and the immune system. In particular these genes affect the seals at the junctions between the cells of the epithelium.

Miles Parkes, Consultant Gastroenterologist at Addenbrookes Hospital and the University of Cambridge, who worked on the study, said, “We have long suspected that genetic defects in the epithelial barrier are important in ulcerative colitis. This large scale genetic study provides the first robust genetic evidence that this is the case.”

Of particular interest is the discovery that CDH1 may be involved in ulcerative colitis. CDH1 encodes the protein E-cadherin, which is involved in building and repairing the epithelium. The gene is known to be less active in areas affected by ulcerative colitis and the loss of this protein has also been implicated in the spread of colon cancer. This provides the first genetic link between the two conditions.

In a second study, researchers, including the International IBD Genetics Consortium, scanned the genomes of over 3,400 patients with childhood IBD and almost 12 ,000 controls. This is by far the largest genetic study to date of childhood-onset disease.

The researchers found five new genetic regions associated with susceptibility to childhood IBD. One of these was close to the gene IL27. This gene is part of a pathway already heavily implicated in adult-onset IBD, which triggers inappropriate activation of the immune cells in the gut.

The genome scans also highlighted the close relationship between how disease occurs in both childhood and adult-onset IBD: multiple regions previously implicated in adult-onset IBD were also detected in this new study.