Study Identifies Genetic Variant that Increases Risk of Severe IBD

A recent study gave new insights into the cause of severe inflammatory bowel disease (IBD), identifying a genetic variant associated with an increased risk for perianal Crohn's disease,

Published in the journal GUT, the investigation was conducted by researchers from Cedars-Sinai Medical Center in Los Angeles, Calif. The study aimed to understand better the pathology of perianal Crohn's disease, defined by authors as a complication of Crohn's disease that results in inflammation and ulceration of the skin around the anus and other structures in the perianal area.

"Fistulizing perianal Crohn's disease can be a really miserable condition," said co-senior author of the study Dermot McGovern, MD, PhD, director of Translational Research in the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute. "Our current therapies are really not very good at treating it; consequently, this study addresses a very significant area of unmet medical need. By gaining an understanding about the underlying causes, we can begin to develop new treatment strategies for patients diagnosed with this chronic inflammatory condition, the majority of whom currently require surgery and often require multiple surgeries.”

To gain more insight into the disease's etiology, McGovern and his colleagues analyzed genetic data from three independent cohorts of patients with Crohn's disease. Of the patients, 4,000 were diagnosed with perianal Crohn's disease and 11,000 were not. 

Researchers compared the cohorts to detect areas of the genome associated with the development of perianal Crohn's called genetic loci. After analysis, they identified ten novel genetic loci and 14 known inflammatory bowel disease loci. Then, during functional characterization analysis, researchers focused on a single-nucleotide polymorphism (SNP) associated with perianal Crohn's disease. They found the genetic variant leads to a loss of function of Complement Factor B (CFB), a protein that's part of the alternative pathway of complement activation, which is important for fighting infections. A loss infection of CFB could lead to several diseases, including perianal Crohn's.

"In the case where you have this mutation that leads to a nonfunctional protein, you don't get the normal signaling cascade, and the body doesn't recognize the bacteria as being harmful, and thus those bacteria are not eliminated," said co-senior author Kathrin Michelsen, PhD, a research assistant professor of Medicine and Biomedical Sciences at Cedars-Sinai. "So, for those patients who have perianal Crohn's disease, there are connections that form from the rectum to the skin area. And those tunnels are full of bacteria that are not being eliminated."

According to Michelsen, the study demonstrates the role of CFB in the development of perianal Crohn's disease. These results, she said, also indicate that targeting the alternative complement pathway should be considered in future therapies for the debilitation condition.