About 5% of the world’s population, and one in ten people in the UK, are currently affected by an autoimmune disease, such as IBD, the umbrella term for Crohn’s disease and ulcerative colitis. These diseases are also becoming more common, with over half a million people living with IBD in the UK as of 2022, nearly double the 300,000 previously estimated.
Despite increasing prevalence, current treatments do not work in every patient and attempts to develop new drugs often fail due to our incomplete understanding of what causes IBD.
Thus, the NIHR BioResource set up an IBD cohort in 2016, with the aim to recruit 50,000 IBD patients for recall studies which aim to improve understanding into the condition and develop treatment better outcomes. To date, more than 47,000 patients have joined and donated DNA samples.
New research discovering major cause of IBD
Published in Nature today, a new research study funded by Crohn's and Colitis UK, the Wellcome Trust, MRC, and Cancer Research UK as well as collaborators across the UK and Europe, used blood samples from BioResource volunteer participants, both with and without IBD. Working with UCL and Imperial College London, scientists at the Crick journeyed into a ‘gene desert’ – an area of DNA that doesn’t code for proteins – which has previously been linked to IBD and several other autoimmune diseases.
They found that this gene desert contains an ‘enhancer’, a section of DNA that is like a volume dial for nearby genes, able to crank up the amount of proteins they make. The team discovered that this particular enhancer was only active in macrophages, a type of immune cell known to be important in IBD, and boosted a gene called ETS2, with higher levels correlating with a higher risk of disease.
Using genetic editing, the scientists showed that ETS2 was essential for almost all inflammatory functions in macrophages, including several that directly contribute to tissue damage in IBD. Strikingly, simply increasing the amount of ETS2 in resting macrophages turned them into inflammatory cells that closely resembled those from IBD patients.
The team also discovered that many other genes previously linked to IBD are part of the ETS2 pathway, providing further evidence that it is a major cause of IBD.
James Lee, Group Leader of the Genetic Mechanisms of Disease Laboratory at the Crick, and Consultant Gastroenterologist at the Royal Free Hospital and UCL, who led the research, spoke on the role of the BioResource:
"Studying how genetic variants contribute to human disease would be almost impossible without having access to fresh samples from people who carry specific DNA changes.
"The NIHR BioResource makes this possible, and helped us show that people with IBD who carry a particular mutation are primed for greater inflammatory responses."
The primary author of the publication, PhD student Christina Stankey, will be presenting this research and our role in facilitating it at this year's BioResource Scientific Conference on Wednesday 19th June 2024. So, if you're interested in finding out more, please register to attend the free virtual event!
ETS2 as a treatment target
Specific drugs that block ETS2 don’t exist, so the team searched for drugs that might indirectly reduce its activity. They found that MEK inhibitors, drugs already prescribed for other non-inflammatory conditions, were predicted to switch off the inflammatory effects of ETS2.
The researchers then put this to the test, and discovered that these drugs not only reduced inflammation in macrophages, but also in gut samples from patients with IBD.
As MEK inhibitors can have side effects in other organs, the researchers are now working with LifeArc to find ways to deliver MEK inhibitors directly to macrophages.
James Lee said:
"IBD usually develops in young people and can cause severe symptoms that disrupt education, relationships, family life and employment. Better treatments are urgently needed.
"Using genetics as a starting point, we’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases. Excitingly, we’ve shown that this can be targeted therapeutically, and we’re now working on how to ensure this approach is safe and effective for treating people in the future."
Christina Stankey, PhD student at the Crick, and first author, said:
"IBD and other autoimmune conditions are really complex, with multiple genetic and environmental risk factors, so to find one of the central pathways, and show how this can be switched off with an existing drug, is a massive step forwards."
Ruth Wakeman, Director of Services, Advocacy and Evidence at Crohn's & Colitis UK said:
"Every year, more than 25,000 people are told that they have Inflammatory Bowel Disease.
"Crohn's and Colitis are complex, lifelong conditions for which there is no cure, but research like this is helping us to answer some of the big questions about what causes them.
"The more we can understand about Inflammatory Bowel Disease, the more likely we are to be able to help patients live well with these conditions.
"This research is a really exciting step towards the possibility of a world free from Crohn's and Colitis one day."
Why have we evolved to carry a genetic variant linked to chronic inflammation?
The unusual thing about the disease variant in the ETS2 enhancer is that it is very common, with approximately 95% of people with IBD carrying one or two copies of it.
Pontus Skoglund and Leo Speidel in the Ancient Genomics Laboratory at the Crick, which studies ancient DNA, worked with James to shed light on when this genetic variant first appeared, showing that it’s incredibly old, at least 500,000 to one million years old, and was even present in Neanderthals and other archaic humans.
They found that the reason this variant remains so common is because switching on ETS2 appears to be an important part of the early response to bacterial infection. Before antibiotics, this may have had a protective effect during infections, which is probably why so many of us still carry the risk variant today, and why it is even commoner in regions with high rates of infectious diseases.
Find out more about the BioResource
If you are a researcher interested in working with the NIHR BioResource to support your work, please get in touch.
To find out more about our work around inflammatory bowel disease or to join the IBD cohort, please contact our team at ibd@bioresource.nihr.ac.uk or take a look at our web pages for more information.
If you are interested in volunteering with the BioResource to be part of future research we support, whether or not you have a health condition, we’d love to hear from you.
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