Cedars-Sinai investigators have identified a genetic variant that increases people’s risk of developing perianal Crohn’s disease (pCD), the most debilitating manifestation of the inflammatory bowel disease (IBD). Their studies involving the analysis of data from thousands of Crohn’s disease subjects, showed that the variant in the complement factor B (CFB) gene generates changes to DNA that lead to a loss of protein function, which in turn alters how the body recognizes and handles bacteria, making it less effective at fighting infections.

“Fistulizing perianal Crohn’s disease can be a really miserable condition,” said Dermot McGovern, MD, PhD, 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 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.” McGovern is co-senior author of the team’s published paper in Gut, which is titled “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.” In their paper, the team noted, “This study suggests that targeting the alternative complement pathway may be a novel therapeutic approach for treating this disabling manifestation of CD.”

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 treatment responses, resulting in a poor quality of life. “Perianal CD (pCD) is, arguably, the most debilitating manifestation of CD associated with significant morbidity, poor response to current therapies, need for surgery (often recurrent), and is, therefore, an area of significant unmet medical need,” the authors wrote.

Over the past decade, genome-wide association studies have implicated more than 240 loci in IBD, yet, as the team continued, “there is a paucity of data understanding the functional effects of these variants and the underlying biology.”

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

To discover genetic variants with a direct tie to this severe manifestation, investigators analyzed genetic data from three independent cohorts of patients with Crohn’s disease. These included the Cedars-Sinai Medical Center MIRIAD IBD Research Repository, the International IBD Genetics Consortium (IIBDGC), and the Sinai-Helmsley Alliance for Research Excellence (SHARE) consortium. “This study is the largest genetic study, to date, specifically studying pCD,” the scientists stated. The three study cohorts totaled 4,000 patients with perianal Crohn’s disease and more than 11,000 Crohn’s disease patients without this complication. “CSMC, IIBDGC, and SHARE had a total of 2,315, 10,738, and 2,091 subjects with CD, respectively,” the investigators noted. “Perianal involvement across these cohorts ranged from ~17–31% of the study population.”

For their study, the researchers compared the cohorts to see if they could detect genetic loci, associated with developing this manifestation. They identified 10 novel genetic loci and 14 known inflammatory bowel disease loci that were associated with the development of perianal complications.

The genetic association analyses highlighted Complement Factor B as “a promising candidate” for functional analyses, and they identified a missense variant (rs4151651) in CFB that was associated with perianal Crohn’s disease. “This variant has previously been strongly associated with CD colonic disease location, complicated CD disease behavior, UC colectomy, and UC age of diagnosis,” they noted. “Previous GWAS have identified associations of CFB with multiple inflammatory diseases in addition to IBD including age-related macular degeneration, anterior uveitis, and systemic lupus erythematosus.” However, they further pointed out, “… the functional consequences of CFB rs4151651 were not previously elucidated.”

The CFB variant, the investigators found through their analyses, leads to a loss of function of the protein, which normally plays a role in fighting infections, and this may be linked to why patients with this genetic change are more likely to have the condition. The rs4151651 leads to glycine to serine amino acid substitution in CFB (G252S CFB), resulting in impaired binding to complement factor 3b and subsequent cleavage of the protein. Tests suggested the mutation is associated with impaired activation of the alternative complement pathway, and reduced macrophage phagocytosis.

The investigators performed multiple analyses to confirm that there really is a loss of function in CFB, which can have a dramatic 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,” said co-senior author of the study Kathrin Michelsen, PhD, 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 also noted the study demonstrates an important role for the alternative complement pathway and CFB in the development of perianal Crohn’s disease. The findings suggest that targeting the alternative complement pathway may be a novel therapeutic approach for treating this disabling manifestation of Crohn’s disease. “In conclusion, we identified clinical characteristics, serological markers, and novel genetic signals associated with pCD,” they wrote. “pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD etiology,” they concluded. Our findings define a critical function of the alternative complement pathway and CFB in pCD by regulating microbial phagocytosis.”

McGovern added, “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.” 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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