Study identifies genetic marker associated with severe IBD

In the largest genetic study of inflammatory bowel disease (IBD) traits to date, researchers have identified a genetic marker that is associated with more severe ulcerative colitis and Crohn's disease – the major forms of IBD.

Researchers from the Wellcome Sanger Institute, the Francis Crick Institute and the NIHR IBD BioResource genetically analysed samples from over 43,000 patients from more than 100 hospitals.

For the first time, the team identified a combination of genetic variants within the HLA-DRB1 gene – known collectively as HLA-DRB1*01:03 – that is associated with more severe disease in people living with IBD.

The results, published today (15 June) in The Lancet Gastroenterology and Hepatology, suggest that genetic testing could identify IBD patients at risk of severe disease, meaning they could be monitored more closely and given advanced therapies earlier.

Over half a million people in the UK are estimated to be living with Crohn's disease and ulcerative colitis¹. These are painful, debilitating and lifelong conditions with no known cure, which cause ulceration and inflammation in the gut.

Treatments for Crohn's disease and ulcerative colitis depend on how severe the symptoms are and how much of the gut is affected. Patients are given medicines that reduce inflammation in the gut, including immunosuppressants and monoclonal antibody therapies, and in more severe cases, surgery may also be required².

The course of disease in IBD is very unpredictable. Some patients experience mild symptoms, including diarrhoea, cramps and fatigue, while others have frequent flare ups or develop much more severe disease that significantly impairs their quality of life.

To understand the role of genetics in IBD, Sanger Institute scientists and their collaborators studied data from 43,762 patients from the NIHR IBD BioResource and UK IBD Genetics Consortium³ – including 21,839 individuals with Crohn's disease and 21,923 individuals with ulcerative colitis or unclassified IBD.

The researchers found that HLA-DRB1*01:03 was present in approximately one in 20 IBD patients and associated with multiple severe outcomes. This included the need for removal of part or all of the colon in those with Crohn's disease and ulcerative colitis as well as individuals with perianal disease – a condition affecting the skin and tissue around the anus. There was also increased need for advanced therapies in patients positive for HLA-DRB1*01:03.

Genetic testing of patients to see if they carry this combination of genetic variants could help identify those who are predisposed to more severe IBD, so that they can be monitored closely and given advanced treatments earlier.

Dr Qian Zhang, first author at the Wellcome Sanger Institute, said: "We have undertaken the largest genetic study of IBD traits to date, involving data from more than 43,000 patients. With this large cohort we were able to find that a combination of genetic variants known as HLA-DRB1*01:03 is linked to more severe disease, not only in ulcerative colitis patients, but also in those with Crohn's disease."

Dr Laura Fachal, co-senior author at the Wellcome Sanger Institute, said: "We found that IBD patients with these genetic variants within the HLA-DRB1 gene had more severe disease, including colon surgeries or advanced treatments, sometimes earlier in their disease progression. Genetic testing to see if patients carry these genetic variants may in future help inform treatment decisions, potentially supporting earlier access to advanced treatments. It could also help identify those at a lower risk of severe disease, where conventional treatments might be sufficient."

Professor James Lee, co-senior author at the Francis Crick Institute, said: "IBD can look very different for different people, and we don't fully know why. Some patients experience mild symptoms, whereas others develop severe disease and require advanced treatments or surgery. This study brings us one step closer to personalised medicine, and to building predictors of disease severity in IBD patients. In the future, patients with increased risk of severe disease could be given advanced treatments earlier, to help improve their quality of life."

Imogen's story

Imogen was diagnosed with atypical ulcerative colitis at age 13 and underwent major surgeries, including a total colectomy, which unfortunately did not improve her symptoms. Her diagnosis was later changed to Crohn's disease and after multiple surgeries and trying several different immunosuppressant medications, Imogen's symptoms are now relatively stable.

Now aged 26, and a first-year medical student, Imogen does experience flare-ups of her symptoms around stressful periods, such as exams, which are disruptive to her day-to-day plans. In addition, her mother and brother have both been diagnosed with IBD in the last two years, but experience very different symptoms of the disease.

Imogen said: "IBD doesn't look the same for everyone. My mum and brother also have it, and we have completely different triggers and symptoms, which vary day to day as well. It's very unpredictable. I cycled through a lot of medications that didn't work, or stopped working after a while. This new research is really exciting, and I hope it will eventually lead to some kind of targeted treatment. If the correct treatment could be identified earlier, it could save a lot of time and suffering for people living with IBD. I'm happy that the research and knowledge around Crohn's disease is still evolving – it leaves me hopeful for the future."

Source:

Wellcome Trust Sanger Institute

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