Insights Into the Underlying Causes of Perianal Crohn’s Disease Could Help Develop Better Treatments
A groundbreaking study conducted by researchers at Cedars-Sinai has uncovered a significant breakthrough in understanding the root cause of perianal Crohn’s disease, a severe form of inflammatory bowel disease.
By analyzing genetic data from thousands of patients with Crohn’s disease, the team identified a genetic variant that increases the risk of developing the condition. The variant alters the body’s ability to handle bacteria, leading to a loss of protein function that makes it less effective at fighting infections.
The findings, published in the reputable GUT journal, have the potential to revolutionize treatment strategies for this chronic inflammatory condition and improve the quality of life for millions of people affected by it.
“Fistulizing perianal Crohn’s disease can be a really miserable condition,” says co-senior author Dermot McGovern.
“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.”
Perianal Crohn’s disease is a serious complication of Crohn’s disease, a chronic inflammation of the digestive tract. It causes inflammation and ulceration of the skin around the anus and other structures in the perianal area. This condition affects up to 40% of individuals with Crohn’s disease, and current treatments are often ineffective, leading to a poor quality of life.
Talin Haritunians, PhD, a research assistant professor at the McGovern Laboratory and co-first author of the study, noted that while identifying genetic variants associated with disease risk has become more common, their study focused on a severe and complex manifestation of Crohn’s disease, which is an unusual approach in genetic research.
Researchers examined genetic data from three distinct groups of patients with Crohn’s disease to pinpoint genetic variants linked to the severe manifestation of perianal Crohn’s disease.
The study cohorts included a Cedars-Sinai cohort, an international genetics cohort from over 20 countries, and a cohort from seven academic research medical centers across the US.
Collectively, the study analyzed genetic data from 4,000 patients with perianal Crohn’s disease and over 11,000 Crohn’s disease patients who did not exhibit this complication.
By comparing the cohorts, the team of scientists aimed to identify genetic loci, or specific areas of the genome associated with developing this severe manifestation.
In their research, the team identified 10 new genetic loci and 14 known inflammatory bowel disease loci that could be linked to the development of perianal complications. The team then conducted a functional characterization analysis, focusing on a single change in a specific gene called an SNP.
This change was found to affect a protein called Complement Factor B (CFB), which is vital for fighting infections. The loss of function in this protein caused by the genetic variant could explain why patients with this change are at higher risk of perianal Crohn’s Disease. The team carried out multiple analyses to confirm the loss of function, which can have a significant impact on the body.
“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,” adds co-senior author Kathrin Michelsen. “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 highlights the significant role of the alternative complement pathway and CFB in the development of perianal Crohn’s disease. The results also suggest that targeting the alternative complement pathway could be a new and innovative therapeutic strategy for managing this debilitating manifestation of Crohn’s disease.
Furthermore, this genetic variant may also have links to other diseases, as per the findings.
“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,” points out McGovern.
Researchers are currently in the process of determining the role of other genetic variants that are linked to perianal Crohn’s disease and other areas where medical needs are yet to be fulfilled in inflammatory bowel diseases.
Source: 10.1136/gutjnl-2023-329689
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