Looking at genetic variations that cause Crohn’s and Colitis

What is this research looking at?

Differences between individuals such as eye colour, hair colour and height are due to tiny parts of DNA that vary between people – known as genetic variations. Genetic variations are a major focus of Crohn's and Colitis research, as they can affect your chance of developing these conditions. If scientists could identify the particular genetic variations that contribute to Crohn's and Colitis, they could learn more about what causes these conditions to develop and discover better treatments. 

More than 200 genetic variations have been found that affect your risk of developing Crohn's or Colitis – but scientists have been unable to figure out what these variations do, or how they contribute to someone developing Crohn's or Colitis. These studies are very difficult, and until recently researchers could only study one genetic variation at a time, making this type of research very slow. 

However, a new technique developed at Harvard University allows researchers to test hundreds of genetic variations at the same time. The scientist leading this research project spent 2 years at Harvard learning this technique, so he can use it to study genetic variations in Crohn's and Colitis. He hoped to discover the pathways inside the body that are disrupted by each genetic variation, so we can better understand what goes wrong when Crohn's and Colitis develop.    
 

What did the researchers find?

The researchers were interested in genetic variations in specific areas of DNA called enhancers. Enhancers are bits of DNA that can turn up the expression of nearby genes – increasing the function of those nearby genes

They looked for genetic variations in the enhancers of a specific type of immune cell called a T cell – known to play a central role in the inflammation in Crohn’s and Colitis.

They found one specific genetic variation that was responsible for a large reduction in enhancer activity – meaning the function of nearby genes was reduced. This is the first time this genetic variation has been linked to Crohn’s and Colitis.

They also found another genetic variation that stopped the binding of a specific protein. The binding of this specific protein usually stops T cells from causing inflammation – and without this stop signal, T cell inflammation continues uncontrolled. This genetic variation has been linked to six immune-mediated diseases, including Crohn’s and Colitis – and partly explains why people with these conditions experience ongoing inflammation.
 

What do researchers think this could mean for people with Crohn's and Colitis?

The researchers have identified key pathways in the body that are involved in the development of Crohn's and Colitis – based on genetic variations found in people with these conditions. They hope this leads to the discovery of better treatments to target these specific pathways, which might also be useful for people with other immune-mediated diseases. This will be an improvement on current treatments that are often less targeted, leading to unwanted side effects.

Scientific publications

Resolving mechanisms of immune‐mediated disease in primary CD 4 T cells (full paper available to read for free)
Main findings:

• The researchers show that a new specialised technique can tell us valuable information about genetic variations in a type of immune cell called a T cell, as well as how these genetic variations change the behaviour and function of the T cells

• They used the technique to identify a specific genetic variation that leads to T cell-driven inflammation – which could predispose people to immune-mediated diseases like Crohn's and Colitis

   

Who is leading this research:  Dr James Lee, University of Cambridge 
Our Funding: £87,463 
Duration: 24 months 
Official title of application: From genetic variants to a better understanding of IBD susceptibility – functional characterisation of non-coding GWAS hits.