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 infl ammatory processes and the generation of a stable fi brin network is necessary for suffi cient infl ammation control. As the density and stability of fi brin networks depend on complex interactions between factor XIIIA (F13A) and fi brinogen genotypes, the authors studied whether these genotypes were related to C-reactive protein (CRP) levels during acute-phase reactions. Methods Association between α-fi brinogen (FGA), β-fi brinogen (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 signifi cant heterogeneity between F13A 34VV and F13A 34L genotypes (p<10 −5 , p adj =0.001). In both cohorts, mean CRP levels signifi cantly 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 identifi ed. Presumably, these haemostatic gene variants modulate infl ammation by infl uencing fi brin crosslinking. These fi ndings could give new perspectives on the genetic background of infl ammation control.Fibrin crosslinking by factor XIII is of crucial importance not only for haemostasis but also for infl ammation control. 1 Several aspects of infl ammatory processes including chemotaxis, 2 3 cell adhesion and migration [4][5][6][7] as well as the antimicrobial host defence 1 8-10 are dependent on or at least significantly infl uenced by fi brin(ogen) and its derivatives. In this context fi brin(ogen) functions as a modulator of different types of cell-cell interactions. 7 11 12 Finally, fi brinogen is involved in the pathogenesis of rheumatoid arthritis (RA), [13][14][15] and it is a target of anticitrullinated protein antibodies (ACPA), which characterise a clinically more severe subset of RA. 16 The architecture of the fi brin gel is a major determinant of clot rigidity and fi brinolysis resistance. 17 It depends on complex interactions between environmental and genetic factors. 18 There are two well-characterised determinants of the fi brin gel architecture. On the one hand, the fi brin gel structure is critically infl uenced by fi brinogen levels, which themselves exhibit a relevant genetic background. [17][18][19] Therefore, variants located in the fi brinogen gene loci, ...

The role of factor XIII-A in the development of inflammatory skin lesions

“…The expression of FXIII-A specific mRNA in a number of monocyte-derived macrophages including tumor macrophages, histocytes, dendritic reticulum cells, perivascular dendritic macrophages, and dermal dendrocytes was demonstrated, and their responsibility for the FXIII-A synthesis was strongly suggested [6,8,12,15,[22][23][24][25]. It was also observed that induction of monocytes differentiation into antigen presenting dendritic cells resulted in highly elevated FXIII-A expression, and its crucial role by fibrin crosslinking in this transformation was suggested.…”

“…The density and stability of fibrin networks depend on FXIIIA. In the study conducted by Hopped et al [23], FXIII-A gene variants modulating inflammation by influencing fibrin crosslinking were identified. These haemostatic gene variants as novel genetic determinants of C-reactive protein (CRP) in inflammatory process were considered.…”

Was sollte der Rheumatologe über Hämostaseologie wissen?

“…"positiver feed forward loop" zwischen inflammatorischer und Gerinnungsaktivierung [1]. Hier konnten wir kürzlich genetische Polymorphismen im Faktor XIII-A und Fibrinogen alpha sowie beta identifizieren, die auf eine deutliche Beziehung zwischen CRP-Spiegel und dem Grad der Entzündung hinweisen [2]. [4].…”

“…Die erhöhten Inzidenzen von venösen Verschlußereignissen ( • ▶ Tab. 1) wurde kürzlich für die meisten entzündlich-rheumatischen Erkrankungen im Vergleich zu Gesunden umfassend in einer Metaanalyse publiziert [6] 1,8 (1) 1,0 (2) 6,7 verordnet werden. Aus rheumatologischer Sicht muss bei entzündlich-rheumatischen Erkrankungen auf das erhöhte Blutungsrisiko unter den traditionellen NSAR hingewiesen werden und nach Möglichkeit Analgetika sowie Coxiben der Vorzug zu geben.…”

Angiotensin converting enzyme intron 16 insertion/deletion genotype is associated with plasma C-reactive protein concentration in uteroplacental dysfunction

“…As CRP levels are critically influenced by a multitude of environmental factors, which are nearly uncontrollable, we used a time-averaged approach including all CRP measurements and adjusted for non-independent observations. 19 Analyses were performed on 639 patients with a total of 2333 CRP measurements (number of presentations: one (n=72), two (n=147), three (n=103), four (n=98), more than four (n=219)). Five hundred and sixty-five patients (88%) were of German origin and the other women were of Middle East and Asian origin.…”