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

Abstract

ObjectivePerianal Crohn’s disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP inComplement Factor B(CFB).DesignImmunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum fromCFBrisk, or protective CD or healthy subjects was assessed by flow cytometry.ResultsPerianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) inCFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum.ConclusionpCD-associated rs4151651 inCFBis 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 aetiology.

Unraveling breast cancer prognosis: a novel model based on coagulation-related genes

“…The complement factor B encoded by the CFB is a component of the alternative pathway of complement activation ( Akhlaghpour et al, 2023 ). Its subunits cleaved by factor D associated with the proliferation and differentiation of pre-activated B lymphocytes, rapid expansion of peripheral blood monocytes, stimulation of lymphocyte follicle formation, and erythrocyte lysis.…”

The Genetics of Inflammatory Bowel Disease

“…Newer data point to an important role of a SNP in Complement Factor B. The non-synonymous variant rs4151651 in Complement Factor B has been associated with perianal CD in three independent cohorts [ 73 ]. Presumably, the genetic contribution to the pathogenesis of EIM and IBD is a combination of overlapping and independent gene loci, reflecting the occurrence of EIM that parallel and do not parallel intestinal inflammation [ 74 ].…”

Systemic Dosing of Virus-derived Serpin Improves Survival and Immunothrombotic Damage in Murine Colitis

“…Of the two primary manifestations of this condition, Crohn's disease (CD) is characterized by transmural inflammation that can affect any region of the gastrointestinal tract, whereas the inflammation in ulcerative colitis (UC) is more superficial and limited to the rectum and colon. In severe IBD there is an elevated risk for both clotting and bleeding, with ongoing immune-mediated damage in the gut and in the vasculature, with relapsing chronic inflammation of the gastrointestinal tract driven by neutrophils, macrophages and T cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…The pathogenesis of IBD is not fully understood, but it is accepted that genetic susceptibility, microvascular inflammation and ischemia, and altered microbiome composition can induce or exacerbate IBD, resulting in a dysregulated immune response (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Increased levels of urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR), as well as fibrinogen are also detected in the colon and in the circulation in IBD (7)(8)(9)(10), underscoring the dysregulated inflammatory and coagulopathic responses.…”

“…Active IBD is also complicated by accelerated atherosclerotic cardiovascular disease and increased risk for thrombotic arterial occlusions (heart attacks) and venous thrombosis (DVT). Immune and coagulation pathways throughout the vascular system are driven by serine protease enzyme cascades in the thrombotic and thrombolytic (coagulation) (7)(8)(9)(10) and complement pathways (11)(12)(13)(14)(15)(16). Serine protease inhibitors, termed serpins, are important endogenous regulators of these protease pathways (17).…”