New Insights On The Cause of Perianal Crohn’s disease

Cedars-Sinai researchers discovered a genetic variation that increases the likelihood of developing perianal Crohn’s disease, the most devastating form of Crohn’s disease.
The variation causes DNA alterations that result in a loss of protein function, altering how the body recognizes and handles bacteria, making it less effective at fighting infections.
The discovery was made public in the journal Gut.

“Fistulizing perianal Crohn’s disease can be a really miserable condition,” said co-senior author of the study Dermot McGovern, MD, Ph.D., director of Translational Research in the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute and the Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics. “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 of 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.”

Perianal Crohn’s disease is a consequence of Crohn’s disease, which is a chronic inflammatory condition of the gastrointestinal tract. Inflammation and ulceration of the skin around the anus, as well as other tissues in the perianal area, are caused by the problem. Perianal Crohn’s disease affects up to 40% of Crohn’s disease patients and has limited therapeutic responses, resulting in a low quality of life.

“We have become much more successful in identifying genetic variants associated with risk of developing diseases, but what we did here is specifically focused on a very complicated and severe manifestation of Crohn’s disease. And that’s an unusual approach in genetic research,” said Talin Haritunians, Ph.D., a research assistant professor who is part of the McGovern Laboratory and co-first author of the study.

Researchers investigated genomic data from three separate cohorts of Crohn’s disease patients to find genetic variations with a direct link to this severe form. A Cedars-Sinai cohort, an international genetics cohort recruited from over 20 nations, and a cohort recruited from seven major research medical institutes across the United States were among the groups. The three groups included 4,000 patients with perianal Crohn’s disease and over 11,000 patients with Crohn’s disease who did not have this consequence.

The researchers compared the cohorts to see whether they could identify genetic loci, which are regions of the genome associated with the development of this manifestation.

The researchers discovered 10 new genetic loci and 14 recognized inflammatory bowel disease loci that are linked to the development of perianal problems.

The scientists concentrated on a single variation in a specific gene, known as an SNP, that was linked to perianal Crohn’s disease during the functional characterization investigation. This genetic variant affects a protein called Complement Factor B (CFB), resulting in a loss of function of this protein, which is critical for combating infections, and may explain why people with this genetic alteration are more prone to have the illness.

The investigators performed multiple analyses to confirm that there really is a loss of function in CFB, which can have a dramatic impact in the body.

“In the case where you have this mutation that leads to a non-functional 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 of the study Kathrin Michelsen, Ph.D., 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.”

Michelsen further stated that the data shows that the alternative complement pathway and CFB play a crucial role in the development of perianal Crohn’s disease. The findings also imply that targeting the alternative complement pathway could be a unique treatment method for treating this debilitating symptom of Crohn’s disease.

This genetic variation has also been linked to other disorders.

“These genetic variants often predispose to more than one condition, and we believe this discovery potentially has ramifications for other diseases as well, not just Crohn’s disease,” said McGovern.

Investigators are now working on identifying the function of additional genetic variants associated with perianal Crohn’s disease and other areas of unmet medical needs in inflammatory bowel diseases.

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