New study sheds light on cause of severe inflammatory bowel disease

Perianal Crohn’s disease is a type of inflammatory bowel disease that affects the area around the anus. It can cause symptoms such as pain, itching and discharge, as well as more serious complications such as abscesses and fistulas.

Scientists at Cedars-Sinai have identified a genetic mutation associated with perianal Crohn’s disease.

Investigator Cedars Sinai We have discovered a genetic variant that makes an individual more likely to experience perianal Crohn’s disease, which is believed to be the most severe form of Crohn’s disease.

A genetic variant is DNA As a result, protein function is lost. This affects the body’s ability to identify and manage bacteria, making it less effective at fighting infections.

Findings will be published in peer-reviewed journals intestine.

“Perianal fistula formation in Crohn’s disease can be a truly devastating condition,” said the study’s co-lead author and director of the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute. Dermot McGovern, MD, Ph.D., Director of Translational Research, said. Joshua L. and Lisa Z. Greer Chair of Inflammatory Bowel Disease Genetics. “This research addresses a very important area of ​​unmet medical need because our current treatments are really poorly suited to treat it. By understanding , we can start developing new therapeutic strategies for patients diagnosed with this chronic inflammatory condition, who now require surgery, often multiple times.”

Perianal Crohn’s disease is a complication of Crohn’s disease, a chronic inflammatory disease that affects the gastrointestinal tract. This complication causes inflammation and ulceration of the skin around the anus and other structures around the anus. Perianal Crohn’s disease affects up to 40% of patients with Crohn’s disease and has limited treatment response, resulting in poor quality of life.

“While we have successfully identified genetic variants associated with risk of developing the disease, what we have done here is specifically focused on the highly complex and severe symptoms of Crohn’s disease. And it’s an unusual approach in genetic research,” said Taryn Harithunians, Ph.D., assistant research professor at the McGovern Institute and co-first author of the study.

To discover genetic variants directly related to this devastating condition, researchers analyzed genetic data from three independent cohorts of Crohn’s disease patients. The groups included the Cedars-Sinai cohort, an international genetics cohort recruited from over 20 countries, and a cohort recruited from his seven academic research medical centers across the United States. The three groups totaled 4,000 perianal Crohn’s disease patients and her over 11,000 Crohn’s disease patients without this complication.

The team of scientists compared cohorts to see if they could detect loci, regions of the genome associated with the development of this sign.

The team identified 10 novel loci and 14 known inflammatory bowel disease loci associated with the development of perianal complications.

During functional characterization, the team focused on single alterations in specific genes, called SNPs, associated with perianal Crohn’s disease. This genetic mutation affects a protein called complement factor B (CFB). This results in the loss of this protein’s function, which is important for fighting infection. This may be why patients with this genetic alteration are more likely to develop the condition.

Researchers have performed multiple analyzes and confirmed that there is indeed a CFB loss of function that can have dramatic effects on the body.

“If you have this mutation that leads to a protein that doesn’t work, you don’t get the normal signaling cascade and the body doesn’t recognize the bacteria as harmful, so those bacteria aren’t eliminated.”-Cedars-Sinai Medicine and Dr. Kathrin Michelsen, research assistant professor of biomedical sciences, said, “So patients with perianal Crohn’s disease have a connection from the rectum to the skin area, and those tunnels are full of unremoved bacteria.”

Michelsen also pointed out that the study points to a critical role for the alternative complement pathway and CFB in the development of perianal Crohn’s disease. The findings also suggest that targeting the alternative complement pathway may be a novel therapeutic approach to treat this impaired manifestation of Crohn’s disease.

This genetic mutation may also be associated with other diseases.

“These genetic variants often predispose to multiple diseases, and we believe this finding may have implications for other diseases, not just Crohn’s disease,” McGovern said. increase.

Researchers are currently working to identify the function of additional gene variants associated with other areas of unmet medical need in perianal Crohn’s disease and inflammatory bowel disease.

Reference: “Genetic coding variants in complement factor B (CFB) are associated with increased risk of perianal Crohn’s disease, leading to CFB cleavage and impaired phagocytosis.” Marzieh Akhlaghpour, Talin Haritunians , Shyam K More, Lisa S Thomas, Dalton T Stamps, Shishir Dube, Dalin Li, Shaohong Yang, Carol J Landers, Emebet Mengesha, Hussein Hamade, Ramachandran Murali, Alka A Potdar, Andrea J Wolf, Gregory J Botwin, Michelle Khrom, International IBD Genetics Consortium, Ashwin N Ananthakrishnan, William A Faubion, Bana Jabri, Sergio A. Lira, Rodney D. Newbery, Robert S. Sandler, R. Balfour Sarter, Ramnik J. Xavier, Stephen A. R. Brandt, Judy H. Cho, Richard H. Duer, Mark G. Lazarev, John D. Liu, L. Phillip Shum, Mark S. Silverberg, Karen Zagyan, Philip Fleshner, Gill Y. Mermed, Eric A. Vasiliuskas, Christina Ha, Shervin Rabizadeh, Gauraf Sial, Nirupama N. Bonsala, David A. Zilling, Stephen R. Targan, Millie D. Long, Dermot PB McGovern, Kathryn S. Michaelsen, 20 April 2023, intestine.
DOI: 10.1136/gutjnl-2023-329689

This research was funded in part by grants from the National Institutes of Health, the F. Widjaja Foundation, the Leona M. And Harry B. Helmsley Charitable Trust, and the Fred L. Hartley Family Foundation.