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Medically reviewed by Dr. Shani S. Saks, D.O. on August 23, 2023

The genetic coding variant rs4151651, in complement factor B, altered complement factor cleavage, alternative pathway activation, and phagocytosis of the pathogen in subjects with perianal Crohn’s disease.

Perianal Crohn’s disease (pCD) is a prevalent condition in CD patients that is related to uncertain causes, limited responses to treatment, and poor quality of life. A genetic-associated study compared patients with pCD and without pCD and investigated the association with complement factor B. 

The findings, published in the journal Gut, indicate that the genetic coding variant rs4151651, associated with pCD in complement factor B, impairs the cleavage of this complement factor, alternative complement pathway activation, and phagocytosis of the pathogen.

Study Characteristics

Perianal involvement in the study population from three cohorts ranged from approximately 17% to 31%, and most of the study population was non-Jewish and of European origin, except for one cohort, which comprised 47% Jewish participants.

CD Colonic Involvement Increases Perianal Crohn’s Disease Risk

Across all the study cohorts, there was a strong association between CD colonic involvement and increased pCD risk. The study subjects with internal penetrating disease had a significantly greater risk of perianal complications compared to those with stricturing disease behavior; however, both conditions had a significantly increased pCD risk compared to inflammatory-only disease.

pCD Linked to IL-2, JAK-STAT, and NF-kB Signaling Pathways

In the context of genetic associations, it was observed that pCD was associated with interleukin 2 (IL-2), Janus kinase/signal transducers and activators of transcription (JAK-STAT), and nuclear factor kappa-light chain-enhancer of activated B cells (NF-kB) signaling pathways. Regarding serological association, antibody positivity is evident in patients with pCD compared to patients without perianal involvement.

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Complement Factor D and Properdin Impact Binding and Cleavage Processes

In the presence of complement factor D and properdin, there was a significant reduction in the binding of S252 with complement factor 3b compared to binding with complement factor B. S252 also abolished complement factor D-dependent cleavage of complement factor B into its subunits. Additionally, the complement factor B genetic coding variant contributed to a significant decrease in the phagocytosis of zymosan particles.


Akhlaghpour, M., Haritunians, T., More, S. K., Thomas, L. S., Stamps, D. T., Dube, S., Li, D., Yang, S., Landers, C. J., Mengesha, E., Hamade, H., Murali, R., Potdar, A. A., Wolf, A. J., Botwin, G. J., Khrom, M., Ananthakrishnan, A. N., Faubion, W. A., Jabri, B., . . . Michelsen, K. S. (2023). 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, gutjnl-329689. https://doi.org/10.1136/gutjnl-2023-329689