Genetic mechanism underpinning inflammatory bowel disease discovered

A new biological pathway linked with inflammatory bowel disease has been discovered, offering new opportunities for treatments.

Researchers have determined how a genetic locus, shown to be associated with a number of inflammatory and autoimmune conditions through genome-wide association studies, could influence risk of developing these conditions due to its interaction with a transcription factor. They have shown how the gene for the transcription factor, ETS2, is overactivated in immune cells and how this can lead to the inflammatory pathways seen in these conditions. They have also shown that readily available drugs can target this pathway, potentially extending the range of treatment options for autoimmune diseases.

'IBD (inflammatory bowel disease) and other autoimmune conditions are really complex, with multiple genetic and environmental risk factors', said Christina Stankey, a PhD student at the Francis Crick Institute and joint first author of the study. '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.'

IBD, which encompasses a range of disorders including Crohn's disease and ulcerative colitis, is becoming increasingly prevalent, and is estimated to affect around half a million people in the UK. While the causes of IBD remain unclear, it is characterised by inflammation of the gastrointestinal tract, and symptoms include pain, diarrhoea and weight loss or, more rarely, constipation.

In research published in Nature, scientists from the Crick Institute, University College London and Imperial College London, among others, investigated an area of chromosome 21 known as a 'gene desert' which, despite having been implicated in IBD, ankylosing spondylitis and several other conditions, doesn't contain any protein-encoding genes.

Here, they found an 'enhancer', a region of DNA which increases the expression of surrounding genes, that was active in immune cells called macrophages. This included the ETS2 gene which, when overactivated in the lab, caused macrophages to resemble those found in affected tissues in people with Crohn's disease.

Around 95 percent of people with IBD carry at least one copy of the genetic variant that leads to activation of the ETS2 enhancer.

Researchers also showed that the ETS2 pathway can be targeted using anti-cancer treatments called MEK inhibitors, which reduced inflammation to the same levels as current IBD treatments. Future research will involve finding ways to limit the side effects of MEK inhibitors by delivering them directly to macrophages.

'What we have found is one of the very central pathways that goes wrong when people get inflammatory bowel disease and this has been something of a holy grail,' said Dr James Lee, a group leader at the Francis Crick Institute and final author of the study.

He added, 'Even for pure, fundamental immunology this is a really exciting discovery. But to show this is dysregulated in people who get the disease not only gives us a better understanding of the disease, it tells us this is something we can treat.'