Complexity of Crohn's disease revealed (7/1/2008)

New research has trebled the number of genetic regions known to be implicated in Crohn's disease, a form of inflammatory bowel disease, to over 30. The large international study involving Oxford University researchers has identified a number of potential new targets for drug development and provided surprising new links between the condition and other common diseases including asthma.

Crohn's disease affects between 1 in 500 and 1 in 1000 people within the UK, causing inflammation of gastrointestinal tract and leading to pain, ulcers and diarrhoea. The disease can strike at any age, but onset is typically between 15 and 40 years old. As many as 80% of people suffering from the disease will require surgery at some point.

Previous studies have already identified 11 genes and loci (regions of the genome typically including one or more genes) that increase susceptibility to the disease. Now an international research collaboration, publishing in the journal Nature Genetics, has identified a further 21 new genes and loci.

The team of scientists and clinicians used DNA samples from almost 12,000 people. Many were from UK patient collections and analysed originally in the Wellcome Trust Case Control Consortium - the largest study ever undertaken into the genetics underlying common diseases - with others coming from European and North American collections.

'We now know of more than 30 genetic regions that affect susceptibility to Crohn's disease,' says Dr Jeffrey Barrett from the Wellcome Trust Centre for Human Genetics at the University of Oxford and lead author of the study. 'These explain only about a fifth of the genetic risk, which implies that there may be hundreds of genes implicated in the disease, each increasing susceptibility by a small amount.'

'While this study shows the power of genome-wide association studies to reveal the genetics behind common diseases, it also highlights the complexity of diseases such as Crohn's.'

Genome-wide association studies have led to an explosion in the number of genes known to be implicated in complex diseases such as diabetes, heart disease and Crohn's disease. The first two Crohn's disease susceptibility genes were discovered in 2001, followed by a third in 2006. The Wellcome Trust Case Control Consortium and parallel studies took that number above 10 the following year using genome-wide association studies. This number has now almost trebled to 32.

Among the findings are loci containing genes known to be implicated in a number of other common diseases including diabetes, rheumatoid arthritis and psoriasis. However, the genetic relationship between Crohn's and these other diseases is not always straightforward. For example, a particular genetic variant called PTPN2 appears to increase susceptibility to both Crohn's disease and type 1 diabetes. But the similarly named PTPN22 increases the risk of developing type 1 diabetes, yet appears to offer protection from Crohn's.

Although some of the disease connections were unsurprising - there is already a known correlation between Crohn's disease and psoriasis, for example - the ORMDL3 gene provided the most unexpected link. ORMDL3 is already known to be a genetic risk factor for childhood asthma, but until now, no epidemiological link had ever been seen between asthma and Crohn's disease.

'It's too early for us to say how Crohn's disease and many of these other diseases, including asthma, are linked at a biological level,' says Dr Miles Parkes, Consultant Gastroenterologist at Addenbrooke's Hospital and the University of Cambridge, who also worked on the study. 'However, we are building up a picture of the biology underlying Crohn's disease, and the more we understand about the underlying biology of these diseases, the better equipped we will be to treat them.'

'Studies such as this are not about developing diagnostic tests, but about identifying targets for new drugs therapies. Crohn's disease can be a very serious condition, often requiring surgery, and the sooner we can understand the underlying causes, the sooner we will be able to devise new treatments to help our patients.'

Some of the most likely candidates for so-called 'druggable' targets include the CCR6 gene, which is thought to be part of the signalling machinery that causes white blood cells in the gut to become over-active, leading to inflammation. These particular white blood cells are also present in inflamed joints, implying that CCR6 may also be relevant to rheumatoid arthritis, and therefore of added interest to the pharmaceutical industry.

Note: This story has been adapted from a news release issued by the University of Oxford

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