Berthold Hoppe1, Christian Schwedler2, Anke Edelmann3, Anneta Pistioli4, Denis Poddubnyy5, Gerd-Rüdiger Burmester6, Thomas Häupl6. 1. Institute of Laboratory Medicine, BG Klinikum Unfallkrankenhaus Berlin gGmbH, Warener Straße 7, 12683 Berlin, Germany; Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany. Electronic address: berthold.hoppe@ukb.de. 2. Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany. 3. Department of Molecular Diagnostics, Labor Berlin - Charité Vivantes GmbH, Sylter Straße 2, 13353 Berlin, Germany. 4. Institute of Laboratory Medicine, BG Klinikum Unfallkrankenhaus Berlin gGmbH, Warener Straße 7, 12683 Berlin, Germany. 5. Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Epidemiology Unit, German Rheumatism Research Centre, Berlin, Charité-Platz 1, 10117 Berlin, Germany. 6. Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Charité-Platz 1, 10117 Berlin, Germany.
Abstract
BACKGROUND: Fibrin(ogen) derivatives, crosslinked fibrin and fibrinolysis play important roles in inflammation and are involved in pathogenesis of rheumatoid arthritis (RA). About 2/3 of RA patients exhibit anti-citrullinated protein antibodies (ACPA) that target deiminated fibrinogen. Genetic variants of β-fibrinogen (FGB) (rs1800790G>A) and factor XIII A-subunit (F13A) Val34Leu (rs5985) are known to influence interactively inflammatory processes. It is hypothesized that predisposition for dense fibrin clots is related to better inflammation control. METHODS: To test this hypothetical model a cohort of 924 patients (288 RA and 636 non-RA patients) (3545 observations) was genotyped for FGB (rs1800790G>A, rs1800788C>T), α-fibrinogen (FGA) (rs6050A>G, rs2070006G>A, rs2070016T>C), γ-fibrinogen (FGG) (rs1049636T>C), F13A Val34Leu (rs5985) and α2-antiplasmin (A2AP) Arg6Trp (rs2070863). Genotype constellations potentially predisposing for dense fibrin clots were defined and their relation to inflammatory activity as measured by C-reactive protein (CRP) and disease activity score of 28 joints (DAS28) was assessed in univariate and multivariate analyses. The relation of these genotype constellations with presence of ACPA was tested. RESULTS: Genotype constellations involving FGB rs1800790G>A and FGA rs2070016T>C were inversely associated with CRP levels (≥10 mg/L) (OR: 0.49, P < 10-8/7adj = 0.0001; OR: 0.52, P < 0.0005/Padj = 0.01). In RA, both genotype constellations were observed with higher frequencies of low disease activity (DAS28 ≤ 3.2) (OR: 2.66, P = .009; OR 2.78, P = .01) and lower frequencies of high disease activity (DAS28>5.1) (OR: 0.52, P < .03, OR: 0.42, P = .01). Associations with CRP depended on A2AP 6Arg/Arg genotype known to be necessary for optimal anti-fibrinolytic capacity (P = .001). Finally, Genotype constellations involving FGB rs1800790G>A and FGA rs2070016T>C were found to be associated with ACPA-positivity in RA (OR: 2.18, P < .03; OR: 1.95, P = .09). CONCLUSIONS: These results support the hypothesis that genotypes, which increase fibrin clot density and anti-fibrinolytic capacity, reduce inflammatory activity and are related to humoral autoimmunity in RA.
BACKGROUND: Fibrin(ogen) derivatives, crosslinked fibrin and fibrinolysis play important roles in inflammation and are involved in pathogenesis of rheumatoid arthritis (RA). About 2/3 of RApatients exhibit anti-citrullinated protein antibodies (ACPA) that target deiminated fibrinogen. Genetic variants of β-fibrinogen (FGB) (rs1800790G>A) and factor XIII A-subunit (F13A) Val34Leu (rs5985) are known to influence interactively inflammatory processes. It is hypothesized that predisposition for dense fibrin clots is related to better inflammation control. METHODS: To test this hypothetical model a cohort of 924 patients (288 RA and 636 non-RApatients) (3545 observations) was genotyped for FGB (rs1800790G>A, rs1800788C>T), α-fibrinogen (FGA) (rs6050A>G, rs2070006G>A, rs2070016T>C), γ-fibrinogen (FGG) (rs1049636T>C), F13AVal34Leu (rs5985) and α2-antiplasmin (A2AP) Arg6Trp (rs2070863). Genotype constellations potentially predisposing for dense fibrin clots were defined and their relation to inflammatory activity as measured by C-reactive protein (CRP) and disease activity score of 28 joints (DAS28) was assessed in univariate and multivariate analyses. The relation of these genotype constellations with presence of ACPA was tested. RESULTS: Genotype constellations involving FGB rs1800790G>A and FGA rs2070016T>C were inversely associated with CRP levels (≥10 mg/L) (OR: 0.49, P < 10-8/7adj = 0.0001; OR: 0.52, P < 0.0005/Padj = 0.01). In RA, both genotype constellations were observed with higher frequencies of low disease activity (DAS28 ≤ 3.2) (OR: 2.66, P = .009; OR 2.78, P = .01) and lower frequencies of high disease activity (DAS28>5.1) (OR: 0.52, P < .03, OR: 0.42, P = .01). Associations with CRP depended on A2AP 6Arg/Arg genotype known to be necessary for optimal anti-fibrinolytic capacity (P = .001). Finally, Genotype constellations involving FGB rs1800790G>A and FGA rs2070016T>C were found to be associated with ACPA-positivity in RA (OR: 2.18, P < .03; OR: 1.95, P = .09). CONCLUSIONS: These results support the hypothesis that genotypes, which increase fibrin clot density and anti-fibrinolytic capacity, reduce inflammatory activity and are related to humoral autoimmunity in RA.