دورية أكاديمية
أعرض في EDS

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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Akhlaghpour M; 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 T; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., More SK; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Thomas LS; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Stamps DT; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Dube S; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Li D; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Yang S; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Landers CJ; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Mengesha E; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Hamade H; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Murali R; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA., Potdar AA; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Wolf AJ; 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 GJ; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Khrom M; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Ananthakrishnan AN; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA., Faubion WA; Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA., Jabri B; Biological Sciences Division, University of Chicago, Pritzker School of Medicine, Chicago, Illinois, USA., Lira SA; Immunology Institute, Mount Sinai Medical Center, New York, New York, USA., Newberry RD; Division of Gastroenterology, Washington Univ. Sch. of Medicine, Saint Louis, Missouri, USA., Sandler RS; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA., Sartor RB; Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA., Xavier RJ; Broad Institute Harvard, Cambridge, Massachusetts, USA., Brant SR; Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA., Cho JH; Genetics and Genomics Sciences, Mt Sinai School of Medicine, New York, New York, USA., Duerr RH; Departments of Medicine and Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Lazarev MG; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Rioux JD; Faculty of Medicine, Universite de Montreal, Montreal, Québec, Canada., Schumm LP; Dept of Health Studies, University of Chicago, Chicago, Illinois, USA., Silverberg MS; Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada., Zaghiyan K; Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA., Fleshner P; Division of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA., Melmed GY; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Vasiliauskas EA; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Ha C; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Rabizadeh S; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA., Syal G; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Bonthala NN; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Ziring DA; Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA., Targan SR; F. Widjaja Inflammatory Bowel Disease Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA., Long MD; Medicine, University of North Carolina, Chapel Hill, North Carolina, USA., McGovern DPB; 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 KS; 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.
مؤلفون مشاركون: International IBD Genetics Consortium
المصدر: Gut [Gut] 2023 Nov; Vol. 72 (11), pp. 2068-2080. Date of Electronic Publication: 2023 Apr 20.
نوع المنشور: Meta-Analysis; Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: British Medical Assn Country of Publication: England NLM ID: 2985108R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-3288 (Electronic) Linking ISSN: 00175749 NLM ISO Abbreviation: Gut Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London, British Medical Assn.
مواضيع طبية MeSH: Complement Factor B*/genetics , Crohn Disease*/complications, Humans ; Quality of Life ; Follow-Up Studies ; Phagocytosis
مستخلص: 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.
Competing Interests: Competing interests: Cedars-Sinai has financial interests in Prometheus Biosciences, a company which has access to the data and specimens in Cedars-Sinai’s MIRIAD Biobank (including the data and specimens used in this study) and seeks to develop commercial products. DM and SRT own stock in Prometheus Biosciences. DL, SRT and DM are consultants for Prometheus Biosciences. DM has consulted for Takeda, Sandoz Immunology, Gilead, Pfizer, Boehringer Ingelheim, Qu Biologics and Bridge Biotherapeutics. CH is on the Advisory Board or consultant for Abbvie, Bristol Myers Squibb, Ferring, Genentech, InDex Pharmaceuticals, Janssen, Pfizer, Takeda, received research support from Abbvie, Genentech, Eli Lilly, Pfizer, and educational grant funding from Pfizer. PF is a consultant for Takeda. GM is a consultant for Abbvie, Arena, Boehringer-Ingelheim, Bristol-Myers Squibb, Janssen, Medtronic, Techlab, Takeda, Pfizer, Samsung Bioepis, Entasis, Ferring, Shionogi and received research funding from Pfizer.
(© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
التعليقات: Comment in: Gut. 2023 Nov;72(11):2010-2012. (PMID: 37098439)
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معلومات مُعتمدة: R01 DK132038 United States DK NIDDK NIH HHS; U01 DK062413 United States DK NIDDK NIH HHS; R01 DK121009 United States DK NIDDK NIH HHS; U01 DK062423 United States DK NIDDK NIH HHS; P01 DK046763 United States DK NIDDK NIH HHS; R01 DK123233 United States DK NIDDK NIH HHS; U01 DK062420 United States DK NIDDK NIH HHS; U01 DK062431 United States DK NIDDK NIH HHS
فهرسة مساهمة: Investigator: C Abraham; JP Achkar; T Ahmad; L Amininejad; AN Ananthakrishnan; V Andersen; CA Anderson; JM Andrews; V Annese; G Aumais; L Baidoo; RN Baldassano; PA Bampton; M Barclay; JC Barrett; TM Bayless; J Bethge; A Bitton; G Boucher; S Brand; B Brandt; SR Brant; C Büning; A Chew; JH Cho; I Cleynen; A Cohain; A Croft; MJ Daly; M D'Amato; S Danese; D Jong; M Vos; G Denapiene; LA Denson; KL Devane; O Dewit; R D'Inca; M Dubinsky; RH Duerr; C Edwards; D Ellinghaus; J Essers; LR Ferguson; EA Festen; P Fleshner; T Florin; D Franchimont; A Franke; K Fransen; R Gearry; M Georges; C Gieger; J Glas; P Goyette; T Green; AM Griffiths; SL Guthery; H Hakonarson; J Halfvarson; K Hanigan; T Haritunians; A Hart; C Hawkey; NK Hayward; M Hedl; P Henderson; X Hu; H Huang; JP Hugot; KY Hui; M Imielinski; A Ippoliti; L Jonaitis; L Jostins; TH Karlsen; NA Kennedy; MA Khan; G Kiudelis; K Krishnaprasad; S Kugathasan; L Kupcinskas; A Latiano; D Laukens; IC Lawrance; JC Lee; CW Lees; M Leja; JV Limbergen; P Lionetti; JZ Liu; E Louis; G Mahy; J Mansfield; D Massey; CG Mathew; DP McGovern; R Milgrom; M Mitrovic; GW Montgomery; C Mowat; W Newman; A Ng; SC Ng; SM Evelyn Ng; S Nikolaus; K Ning; M Nöthen; I Oikonomou; O Palmieri; M Parkes; A Phillips; CY Ponsioen; U Potocnik; NJ Prescott; DD Proctor; G Radford-Smith; JF Rahier; S Raychaudhuri; M Regueiro; F Rieder; JD Rioux; S Ripke; R Roberts; RK Russell; JD Sanderson; M Sans; J Satsangi; EE Schadt; S Schreiber; D Schulte; L Philip Schumm; R Scott; M Seielstad; MS Silverberg; LA Simms; J Skieceviciene; SL Spain; A Hillary Steinhart; JM Stempak; L Stronati; J Sventoraityte; SR Targan; KM Taylor; AT Velde; E Theatre; L Torkvist; M Tremelling; AV Meulen; SV Sommeren; E Vasiliauskas; S Vermeire; HW Verspaget; T Walters; K Wang; MH Wang; RK Weersma; Z Wei; D Whiteman; C Wijmenga; DC Wilson; J Winkelmann; RJ Xavier; B Zhang; CK Zhang; H Zhang; W Zhang; H Zhao; ZZ Zhao
Keywords: IBD - GENETICS; INFLAMMATORY BOWEL DISEASE; META-ANALYSIS
المشرفين على المادة: EC 3.4.21.47 (Complement Factor B)
تواريخ الأحداث: Date Created: 20230420 Date Completed: 20231009 Latest Revision: 20240501
رمز التحديث: 20240501
مُعرف محوري في PubMed: PMC11036449
DOI: 10.1136/gutjnl-2023-329689
PMID: 37080587
قاعدة البيانات: MEDLINE
الوصف
تدمد:1468-3288
DOI:10.1136/gutjnl-2023-329689