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New genetic links to inflammatory bowel disease

30 November 2009
Appeared in BioNews 536

New genetic studies have identified several key genetic regions which could play a role in ulcerative colitus, a common form of inflammatory bowel disease (IBD). All three studies were reported in Nature Genetics on 15 November.

Ulcerative colitis affects approximately one in 1000 people. It is a chronic, debilitating condition in which the colon and rectum become severely inflamed causing ulceration, bleeding, diarrhoea and abdominal pain. Although the cause remains unknown, the disease is known to have a genetic component.

Genome-wide association studies compare the genomes of individuals affected by a disease with healthy controls. If variations in the DNA, called SNPs (pronounced 'snips'), occur more frequently with the disease, it is possible that the nearby genes have a causative or contributing role. Indeed, the last two years has seen several such studies identify approximately 32 genetic regions associated with ulcerative colitis and also Crohn's, another form of IBD.

The present studies were highly powered; not only were they able to identify more genetic regions, but they also went some way to identify several biologically plausible genes which could be involved in disease onset and progression. Some of the candidate genes involve autoimmunity: for example the FCGR2A gene, which encodes a receptor on the surface of several immune cells and the IL27 gene, which encodes a chemical signal or 'cytokine' which regulates immune cells. Other genes identified point to the integrity of the gut lining: the genes LAMB1, CDH1, and HNF4A affect the seals between gut wall cells. When faulty, these seals could allow bacterial penetration from the gut with an ensuing inflammatory response.

Sir Mark Walport, director of the Wellcome Trust, says: 'Although it is a long way from this discovery to developing new treatments for inflammatory bowel disease, new approaches to the treatment and prevention of chronic diseases require new insights into their causes'. Indeed questions have already arisen regarding current and potential treatment. A current treatment uses antibodies against a cytokine called TNF╬▒, the recent research highlights the possibility of using a similar treatment against IL27. Professor Chris Mathew of King's College London, also said the results relating to the gut wall were 'very significant as most treatments to date are based on damping down immune response'. He went on to explain that the data 'suggests there may be mileage in trying to tighten up the mucosal barrier as well'.

One of the studies went further to examine genetic associations with childhood IBD. A lead researcher in the study, Professor Jack Satsangi from the University of Edinburgh, said: 'Childhood IBD is a particularly devastating disease, which inevitably impacts seriously on all aspects of a child's life and indeed on all members of the child's family. Our findings suggest that certain susceptibility genes are more important in children than in adults'.

Professor Satsangi went on to highlight one of the next steps in the research: 'There are now a series of important questions to address, arising from this work. In high-incidence areas such as Scotland, it is especially important now for us to explore the interactions between genes and the environment and understand what triggers this disease in susceptible individuals'.

The scientists hope that this research will help lead targeted treatment in the future. 'This is an evolving story of discovering what genes tell us about the disease,' said Dr Robert N. Baldassano, a co-first author of one of the studies, adding: 'Pinpointing how specific genes act on biological pathways provides a basis for ultimately personalizing medicine to an individual's genetic profile'.

SOURCES & REFERENCES
Gut disorder 'blamed on leaks'
BBC News |  15 November 2009
Largest Gene Study of Childhood Inflammatory Bowel Disease Identifies Five New Genes
ScienceDaily |  16 November 2009
New susceptibility loci associated with IBD
PHG Foundation |  18 November 2009
Powerful genetic studies reveal secrets of adult and childhood inflammatory bowel disease
Wellcome Trust press release |  16 November 2009
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