Two Studies Uncover Genetic Variants Linked to Severe Inflammatory Bowel Disease
Two separate research studies have identified distinct genetic variants associated with more severe forms of inflammatory bowel disease (IBD), covering ulcerative colitis and Crohn's disease. The findings were published in separate medical journals.
Genetic Variant HLA-DRB1*01:03 Linked to Severe Outcomes
Researchers from the Wellcome Sanger Institute, the Francis Crick Institute, and the NIHR IBD BioResource analyzed genetic samples from 43,762 patients across over 100 hospitals. The study identified a combination of genetic variants within the HLA-DRB1 gene, designated HLA-DRB1*01:03, associated with more severe ulcerative colitis and Crohn's disease. The findings were published in The Lancet Gastroenterology and Hepatology on June 15.
"HLA-DRB1*01:03 was present in approximately one in 20 IBD patients."
Key outcomes for carriers of the variant included:
- Increased likelihood of requiring partial or total colon removal
- Higher risk of developing perianal disease
- Greater need for advanced therapies
The association was observed in both Crohn's disease and ulcerative colitis patients.
Background on IBD
IBD, including Crohn's disease and ulcerative colitis, affects over 500,000 people in the UK. The condition causes gut ulceration and inflammation, with no known cure. Disease courses vary widely; some patients have mild symptoms, while others require immunosuppressants, monoclonal antibody therapies, or surgery.
Expert Commentary
Dr. Qian Zhang (first author, Wellcome Sanger) stated that the large cohort enabled linking HLA-DRB1*01:03 to severe disease in both conditions. Dr. Laura Fachal (co-senior author, Wellcome Sanger) noted the variant was associated with colon surgeries and advanced treatments, sometimes early in disease progression.
Professor James Lee (co-senior author, Francis Crick Institute) said the study advances personalized medicine and predictors of disease severity.
Gene OTUD3 Identified as Factor in Ulcerative Colitis
A separate study identified a mutation in the OTUD3 gene linked to ulcerative colitis. Researchers utilized advanced genomic sequencing, comparing DNA from affected and unaffected members of a Brisbane family, in which five members across three generations were diagnosed with the condition. The condition led to surgery for four family members to remove all or part of their bowels.
How the Gene Works
The OTUD3 gene provides instructions for producing a protein vital for the gut's protective barrier. The research indicates that disruption of this barrier can allow bacteria to invade the gut lining, triggering chronic inflammation.
Prevalence and Population Impact
The OTUD3 mutation was found in the Brisbane family and in a subset of other ulcerative colitis patients, based on data from UK and Finnish biobanks. Approximately 0.1 percent of people of South Asian descent carry the mutation.
Dr. Rabina Giri, lead researcher from Mater Research's Inflammatory Bowel Disease Group, stated this is the first study to connect the OTUD3 gene with intestinal health. Previously, the gene was known for its role in cancer biology.
Clinical Implications
Gastroenterologist Jake Begun, who leads Mater Research's Inflammatory Bowel Disease Research Group, noted the study's importance in uncovering chronic disease causes and opening doors for new diagnostic tools and therapies. Professor Albert Lam of Griffith University described the discovery as significant for understanding the bowel barrier.
The findings suggest potential for developing new drugs that could increase expression of the protein produced by OTUD3. Preliminary data indicates some existing drugs may already increase this expression.
Over 100,000 Australians are estimated to be living with IBD. The study was published in the journal Cellular and Molecular Gastroenterology and Hepatology.