Genetics could determine how people respond to treatment

What the research looked at?

Immunosupressant drugs, such as azathioprine (AZA) and mercaptopurine (MP) are commonly used to treat IBD. However, while these two drugs are a very effective treatment, around half of people with IBD fail to respond to them. This is often because people respond to the drug in different ways – and is down to the way each person’s body breaks up the drug once it is in the body. Genetic differences can alter the way that people break down the drug. 

The body metabolises (breaks down) the AZA and MP into two end products – TGN (which is responsible for the beneficial immunosuppressant effect) and MeMP (which is associated with non-response to the treatment, liver toxicity and other side effects). People who fail to respond to AZA and MP are more likely to produce MeMP by a process called hypermethylation. 

However, hypermethylation can be reduced by drugs. A drug called allopurinol can be taken alongside AZA or MP. Allopurinol stops the hypermethylation – so reduces the amount of MeMP produced and thus reduces side effects to the immunosuppressants. 

Unfortunately, at present hypermethylation can only be detected once the patient has been taking the drugs for many months. The aim of this research project is to try and identify any strings of genetic code in patient’s DNA (called genetic markers) that are common among those who don't respond to AZA or MP. 

If a genetic marker can be found, then doctors will be able to predict which patients will not respond to AZA and MP – and know to prescribe them allopurinol to make the treatment more effective and reduce side effects. 

Conclusions: 

The study confirmed that hypermethylation is an important cause of why treatment with AZA or MP fails in patients with IBD. Doctors can check the MeMP:TGN ratio in a patient’s blood a month after they have started them to see which patients are likely to have problems – and if so, whether they should receive allopurinol to reduce the amount of MeMP in the body. 

It would be even more useful to have a test to predict hypermethylation before patients even start taking the drugs. The researchers have identified some new genetic differences which may predict whether hypermethylation will take place in up to a quarter of people. These markers now need to be tested in the hope that they may be able to be used to tailor therapy to individual patients. 

What researchers think this could this mean for people with IBD? 

This research is important since whilst there are many factors influencing outcome on AZA and MP in patients with IBD, hypermethylation is probably the most significant and, critically, can be readily prevented by allopurinol therapy. Hence, in determining a test for hypermethylation at the start of treatment, it is anticipated that the results of this study will translate readily into better treatment for patients with IBD. 

Who led the research: Dr Jeremy Sanderson, Guy's and St. Thomas's Trust Foundation Hospital
Our funding: £59,961 over 12 months
Official title of the application: "Optimising the Response to Thiopurine Therapy in Inflammatory Bowel Disease: a Search for Biomarkers Predicting Thiopurine Hypermethylation."
Tags: Genetics /Drugs