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


METHODS
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.


RESULTS
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)).


CONCLUSIONS
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.
Kovar
Florian M
FM
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Marsik
Claudia
C
Jilma
Bernd
B
Mannhalter
Christine
C
Quehenberger
Peter
P
Handler
Silvia
S
Wagner
Oswald F
OF
Endler
Georg
G
D000328:Adult; D004492:Edetic Acid / Q000737:chemistry; D019446:Endotoxemia / Q000235:genetics*; D005340:Fibrinogen / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D016296:Mutagenesis; D016133:Polymerase Chain Reaction / Q000379:methods*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005340:Fibrinogen; D004492:Edetic Acid