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.
Akhlaghpour, Marzieh; Haritunians, Talin; More, Shyam Ket al.
[en] [en] OBJECTIVE: Perianal 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 in Complement Factor B (CFB).
DESIGN: Immunochip-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 from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry.
RESULTS: Perianal 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) in CFB, 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.
CONCLUSION: 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 aetiology.
Disciplines :
Genetics & genetic processes
Author, co-author :
Akhlaghpour, Marzieh; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA ; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
Haritunians, Talin; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
More, Shyam K; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Thomas, Lisa S; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Stamps, Dalton T; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Dube, Shishir; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Li, Dalin; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Yang, Shaohong; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Landers, Carol J; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Mengesha, Emebet; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Hamade, Hussein ; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Murali, Ramachandran; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
Potdar, Alka A; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Wolf, Andrea J; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA ; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
Botwin, Gregory J; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Khrom, Michelle; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
International IBD Genetics Consortium
Ananthakrishnan, Ashwin N ; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
Faubion, William A; Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
Jabri, Bana; Biological Sciences Division, University of Chicago, Pritzker School of Medicine, Chicago, Illinois, USA
Lira, Sergio A ; Immunology Institute, Mount Sinai Medical Center, New York, New York, USA
Newberry, Rodney D; Division of Gastroenterology, Washington Univ. Sch. of Medicine, Saint Louis, Missouri, USA
Sandler, Robert S; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
Sartor, R Balfour; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
Xavier, Ramnik J; Broad Institute Harvard, Cambridge, Massachusetts, USA
Brant, Steven R; Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
Cho, Judy H ; Genetics and Genomics Sciences, Mt Sinai School of Medicine, New York, New York, USA
Duerr, Richard H; Departments of Medicine and Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Lazarev, Mark G; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Rioux, John D; Faculty of Medicine, Universite de Montreal, Montreal, Québec, Canada
Schumm, L Philip; Dept of Health Studies, University of Chicago, Chicago, Illinois, USA
Silverberg, Mark S; Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Zaghiyan, Karen; Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
Fleshner, Phillip; Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA
Melmed, Gil Y; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Vasiliauskas, Eric A; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Ha, Christina; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Rabizadeh, Shervin; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
Syal, Gaurav; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Bonthala, Nirupama N; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Ziring, David A; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
Targan, Stephan R; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
Long, Millie D; Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
McGovern, Dermot P B; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA kathrin.michelsen@cshs.org Dermot.McGovern@cshs.org ; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
Michelsen, Kathrin S ; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA kathrin.michelsen@cshs.org Dermot.McGovern@cshs.org ; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
Georges, Michel ; Université de Liège - ULiège > GIGA > GIGA Medical Genomics - Unit of Animal Genomics ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale ; International IBD Genetics Consortium
Language :
English
Title :
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.
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