title: Fibrinogen and factor XIII A-subunit genotypes interactively influence C-reactive protein levels during inflammation.
abstract: OBJECTIVE
  Fibrinogen is a target of autoimmune reactions in rheumatoid arthritis (RA). Fibrin(ogen) derivatives are involved in inflammatory processes and the generation of a stable fibrin network is necessary for sufficient inflammation control. As the density and stability of fibrin networks depend on complex interactions between factor XIIIA (F13A) and fibrinogen genotypes, the authors studied whether these genotypes were related to C-reactive protein (CRP) levels during acute-phase reactions.
  
  
  METHODS
  Association between α-fibrinogen (FGA), β-fibrinogen (FGB) and F13A genotypes with CRP levels was tested in two cohorts with longitudinal CRP measurements. Discovery and replication cohorts consisted of 288 RA (913 observations) and 636 non-RA patients (2541 observations), respectively.
  
  
  RESULTS
  Genotype FGB -455G>A (rs1800790) was associated with CRP elevations (≥ 10 mg/l) in both cohorts (RA, OR per allele 0.69, p=0.0007/P(adj)<0.015; non-RA, OR 0.70, p=0.0004/p(adj)<0.02; combined, OR 0.69, p<10(-5)/p(adj)=0.001). Genotype F13A 34VV (rs5985) was conditional for the association of FGB -455G>A with CRP as indicated by a clear restriction on F13A 34VV individuals and a highly significant heterogeneity between F13A 34VV and F13A 34L genotypes (p<10(-5), p(adj)=0.001). In both cohorts, mean CRP levels significantly declined with ascending numbers of FGB -455A alleles. Genotype FGA T312A (rs6050) exhibited opposite effects on CRP compared with FGB -455G>A. Again, this relation was dependent on F13A V34L genotype.
  
  
  CONCLUSIONS
  Novel genetic determinants of CRP completely unrelated to previously known CRP regulators were identified. Presumably, these haemostatic gene variants modulate inflammation by influencing fibrin crosslinking. These findings could give new perspectives on the genetic background of inflammation control.
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. berthold.hoppe@charite.de
authors.forename: Berthold
authors.initials: B
authors.lastname: Hoppe
authors.forename: Thomas
authors.initials: T
authors.lastname: Häupl
authors.forename: Alla
authors.initials: A
authors.lastname: Skapenko
authors.forename: Sabine
authors.initials: S
authors.lastname: Ziemer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Tauber
authors.forename: Abdulgabar
authors.initials: A
authors.lastname: Salama
authors.forename: Hendrik
authors.initials: H
authors.lastname: Schulze-Koops
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Thomas
authors.initials: T
authors.lastname: Dörner
mesh_terms: D000210:Acute-Phase Reaction / Q000097:blood / Q000235:genetics*; D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis*; D026122:Factor XIIIa / Q000032:analysis / Q000235:genetics*; D005260:Female; D005340:Fibrinogen / Q000032:analysis / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D005340:Fibrinogen; D002097:C-Reactive Protein; D026122:Factor XIIIa