New research finds risk and prognosis of Crohn’s Disease determined by different genes

09 January 2017

New research finds risk and prognosis of Crohn’s Disease determined by different genes

Researchers from the University of Cambridge have identified a series of genetic variants that affect the severity of Crohn’s Disease, a form of Inflammatory Bowel Disease – but surprisingly, none of these variants appear to be related to an individual’s risk of developing the condition in the first place.

Crohn’s Disease is one of a number of chronic ‘complex’ diseases for which there is no single gene that causes the disease. In fact, to date around 170 common genetic variants have been identified that each increase the risk of an individual developing the disease.

The conventional wisdom has been that there exists a ‘tipping point’: if someone has enough of these genes, they become very likely to develop the disease – and the more of the variants they carry, the more the severe the disease will then be.

However, in a study published today in Nature Genetics, a team of researchers led by the University of Cambridge and funded by Crohn’s and Colitis UK has shown that this is not the case: genetic variants that affect the progression or prognosis of Crohn's Disease operate independently of those that increase the likelihood of developing the disease in the first place.

“Genetic studies have been very successful at identifying genetic risk factors for Crohn’s Disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition,” says Dr James Lee from the Department of Medicine at Cambridge.

“We do know, though, that family members who have the disease often tend to see it progress in a similar way. This suggested to us that genetics was likely to be involved in prognosis.”

The researchers looked at the genomes – the entire genetic makeup – of more than 2,700 individuals, who were selected because they had either experienced particularly mild or particularly aggressive Crohn’s Disease.

By comparing these patients’ DNA, the researchers found four genetic variants that influenced the severity of a patient’s condition. Strikingly, none of these genes have been shown to affect the risk of developing the disease.

The team then looked at all the known genetic risk variants for Crohn’s and found that none of these influenced the severity of disease.

“This shows us that the genetic architecture of disease outcome is very different to that of disease risk,” adds Professor Ken Smith, Head of the Department of Medicine.

“In other words, the biological pathways driving disease progression may be very different to those that initiate the disease itself. This was quite unexpected. Past work has focussed on discovering genes underlying disease initiation, and our work suggests these may no longer be relevant by the time a patient sees the doctor. We may have to consider directing new therapies to quite different pathways in order to treat established disease.”

“This discovery has shown us a new way of looking at disease and opens up potential new treatment options, which could substantially ease the burden of Crohn’s Disease,” says Dr Lee. “What’s more, we have evidence that some of these prognosis genes will be shared with other diseases, and as such this approach could be used to improve treatment in a number of conditions.”

As well as its implications for Crohn’s and other diseases, the approach taken by the researchers has suggested that there is value in re-examining previous genetic studies. Around a third of the genomes of Crohn’s Disease patients analysed in this study had been collected for a previous study in 2007. By dividing the patients into groups categorised by disease severity, the researchers were able ask new questions – and gain new insights – from the old data.

This is an exciting breakthrough which offers new hope for people who suffer every day from Crohn's and Colitis. The research sheds new light on why some people with Inflammatory Bowel Disease experience more severe symptoms than others which has been little understood until now.

Dr Wendy Edwards 
Research Manager at Crohn’s and Colitis UK