Cedars-Sinai researchers have identified a genetic variant that increases people’s risk of developing perianal Crohn’s disease, the most debilitating manifestation of Crohn’s disease.
The variant generates changes in the DNA that lead to a loss of function of the protein, which in turn alters the way the body recognizes and handles the bacteria, making them less effective in fighting infection.
The discovery is published in the peer-reviewed journal INTESTINE.
“Fistulizing perianal Crohn’s disease can be a truly miserable condition,” said study co-senior author Dermot McGovern, MD, PhD, director of Translational Research at the Cedars-Sinai Foundation’s Gut Inflammation and Immunobiology Research Institute. Widjaja and the Joshua L. and Lisa Z. Greer Chair in the Genetics of Inflammatory Bowel Disease. “Our current therapies really aren’t very good at treating it, so this study addresses a very important area of unmet medical need. By better understanding the underlying causes, we can begin to develop new treatment strategies for patients diagnosed with this disease. chronic inflammatory”. condition, most of which currently require surgery and often require multiple surgeries.”
Perianal Crohn’s disease is a complication of Crohn’s disease, a chronic inflammatory disorder that affects the digestive tract. The complication causes inflammation and ulceration of the skin around the anus, as well as other structures in the perianal area. Perianal Crohn’s disease occurs in up to 40% of people with Crohn’s disease and has limited responses to treatment, resulting in poor quality of life.
“We’ve been much more successful in identifying genetic variants associated with disease risk, but what we did here specifically targeted a very complicated and severe manifestation of Crohn’s disease. And that’s an unusual approach in research. genetics,” said Talin Haritunians. , PhD, a research assistant professor with the McGovern Laboratory and co-senior author of the study.
To discover genetic variants with a direct link to this severe manifestation, the researchers analyzed genetic data from three independent cohorts of Crohn’s disease patients. The groups included a Cedars-Sinai cohort, an international genetics cohort recruited from more than 20 countries, and a cohort recruited from seven academic research medical centers across the United States. The three groups totaled 4,000 patients with perianal Crohn’s disease and more than 11,000 patients with Crohn’s disease without this complication.
The team of scientists compared the cohorts to see if they could detect genetic loci, which are areas of the genome associated with the development of this manifestation.
The team identified 10 novel genetic loci and 14 known inflammatory bowel disease loci associated with the development of perianal complications.
During the functional characterization analysis, the team focused on a single change in a specific gene, called a SNP, that was associated with perianal Crohn’s disease. This genetic variant affects a protein called Complement Factor B (CFB), leading to a loss of function of this protein that is important in fighting infection, so it is possible that patients with this genetic change are more likely to have the condition.
The researchers performed multiple analyzes to confirm that there is indeed a loss of function in the CFB, which can have a dramatic impact on the body.
“In the event that 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 harmful, and therefore those bacteria aren’t killed,” co said. . -Lead study author Kathrin Michelsen, PhD, 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 cleared.”
Michelsen also noted that the study demonstrates an important 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 disabling manifestation of Crohn’s disease.
This genetic variant may also be associated with other diseases.
“These gene variants often predispose to more than one condition, and we believe this discovery has potential ramifications for other diseases as well, not just Crohn’s disease,” McGovern said.
Investigators are now working to identify the role of additional genetic variants associated with perianal Crohn’s disease and other areas of unmet need in inflammatory bowel diseases.
Marzieh Akhlaghpour, PhD, a former graduate student at Cedars-Sinai, was a co-author of the study. Other Cedars-Sinai authors include 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, Gil Y. Melmed, Eric A. Vasiliauskas, Christina Ha, Gaurav Syal, Nirupama N. Bonthala, and Stephan Targan.