The fibrinogen -148 C/T polymorphism influences inflammatory response in experimental endotoxemia in vivo

The acute phase reactant fibrinogen plays a critical role in the coagulation system and inflammation. Recently several polymorphisms have been described regulating basal and peak fibrinogen expression. We evaluated the role of a frequent promoter polymorphism in the beta chain of the fibrinogen gene (-148 C/T) in a human in vivo model of experimental endotoxemia.

Healthy volunteers received 2 ng/kg endotoxin (LPS, n=73) as a bolus infusion over 2 min. Blood samples were collected by venipunctures into EDTA anticoagulated vacutainer tubes before LPS infusion. For determination of the fibrinogen promoter polymorphism, we developed a new mutagenic separated polymerase chain reaction assay.

Carriers of the -148 T allele had significantly lower TNFalpha expression throughout the whole time course of LPS stimulation and Interleukin-6 levels were trendwise lower, however only basal levels reached statistical significance. No effects were observed on markers of coagulation activation (D-Dimer, Prothrombin F(1+2)).

Our findings indicate, that the common -148 C/T polymorphism is associated with differences in the TNFalpha release in response to systemic LPS infusion in humans, and add to current evidence that gene-sequence changes in beta-fibrinogen locus can alter the ability of the host to respond to endotoxin.