New insight into the cause of severe inflammatory bowel disease

Scientists identified genetic variants associated with perianal Crohn’s disease.


Fistulizing perianal Crohn’s disease can be a miserable condition. Existing therapies aren’t effective. A new study addresses a significant area of unmet medical need.

Scientists from Cedars-Sinai have discovered a genetic variation that raises people’s chances of getting perianal Crohn’s disease, the most crippling form of the condition. Researchers can start creating novel treatment plans for individuals with this chronic inflammatory illness, the majority of whom currently require surgery and frequently necessitate repeated surgeries, by learning more about the underlying reasons.

A consequence of Crohn’s disease, a long-term inflammatory condition that affects the digestive tract, is perianal Crohn’s disease. The problem results in skin ulceration and inflammation around the anus and other perianal structures. Up to 40% of persons with Crohn’s disease develop perianal Crohn’s disease, which has poor treatment outcomes and low quality of life.

Talin Haritunians, Ph.D., a research assistant professor who is part of the McGovern Laboratory and co-first author of the study, said, “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.”

Researchers examined the genomic information from three distinct cohorts of Crohn’s disease patients to find genetic variations that had a clear relationship to this severe manifestation. A Cedars-Sinai cohort, an international genetics cohort drawn from more than 20 nations, and a cohort drawn from seven academic research medical centers across the United States were among the groups. Over 11,000 Crohn’s disease patients without this consequence and 4,000 people with perianal Crohn’s disease made up the three groups.

To identify genetic loci—areas of the genome linked to the emergence of this manifestation—the research team studied cohorts.

The group discovered 14 known inflammatory bowel disease loci and ten additional genetic loci linked to the emergence of perianal problems.

During the functional characterization investigation, the group focused on a single SNP, or single nucleotide polymorphism, in a particular gene that was linked to perianal Crohn’s Disease. Patients with this genetic difference may be more prone to illness because this genetic variation affects a protein called Complement Factor B (CFB), which causes a loss of function and is crucial for combating infections.

Scientists conducted numerous investigations to establish that there is, in fact, a loss of function in CFB, which may have a significant effect on the body. 

Co-senior author of the study Kathrin Michelsen, Ph.D., a research assistant professor of Medicine and Biomedical Sciences at Cedars-Sinai, said, “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.”

“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.”

“The study demonstrates an important role for the alternative complement pathway and CFB in developing perianal Crohn’s disease. The findings also suggest that targeting the alternative complement pathway may be a novel therapeutic approach for treating this disabling manifestation of Crohn’s disease.”

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

Scientists 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.

Journal Reference:

  1. Marzieh Akhlaghpour, Shyam K. More, Lisa S. Thomas, Dalton T. Stamps, Shishir Dube, et al. A genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn’s disease and leads to impaired CFB cleavage and phagocytosis. Gut. DOI: 10.1136/gutjnl-2023-329689
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