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/Padj<0.015; non-RA, OR 0.70, p=0.0004/padj<0.02; combined, OR 0.69, p<10−5/padj=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, padj=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.
Conclusion 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.
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Contributors BH developed the hypotheses and conceived and designed the study. GRB, SZ, TD, TH and BH coordinated sample acquisition and laboratory analyses. TD, TH and BH analysed and ASa, ASk, GRB, HSK, RT, TD, TH and BH interpreted the data. BH drafted the manuscript. ASa, ASk, GRB, HSK, RT, TD and TH critically revised the manuscript for important intellectual contents. All authors had full access to all data and approved the final version of the manuscript.
Funding This work was supported by the German Federal Ministry of Education and Research (BMBF) through ArthroMark (grant 01EC1009A).
Ethics approval Ethics approval for this study was obtained from the local ethics committee.
Patient consent Obtained.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.