Marburg I polymorphism of factor VII--activating protease: a prominent risk predictor of carotid stenosis.
BACKGROUND
Atherothrombosis is a main pathomechanism in the evolution of vessel stenosis and is counteracted by endogenous fibrinolysis. Recently, the plasmatic serine protease "factor seven-activating protease" (FSAP) was recognized as a potent activator of prourokinase in vitro. The Marburg I polymorphism of FSAP impairs this potential and may thus facilitate arterial thrombosis.


RESULTS
This analysis of the Bruneck Study involved 810 men and women aged 40 to 79 years. The ultrasound-based atherosclerosis progression model (5-year follow-up) permits differentiation between early atherogenesis and the advanced stenotic stages of carotid artery disease. The FSAP Marburg I polymorphism was found in 37 subjects (carriage rate 4.4%). Individuals with this genetic variant showed a prominently reduced in vitro capacity to activate prourokinase. No relation was found to exist between the Marburg I polymorphism and early atherogenesis. In contrast, it emerged as a strong and independent risk predictor of incident/progressive carotid stenosis (multivariate odds ratio [95%CI], 6.6 [1.6 to 27.7]). This finding equally applied to subjects with and without co-segregation of the Marburg II polymorphism. The risk profile of advanced atherogenesis further includes cigarette smoking, high lipoprotein(a), the factor V Leiden mutation, low antithrombin III, high fibrinogen, and diabetes.


CONCLUSIONS
In concert with other genetic and acquired conditions known to interfere with coagulation or fibrinolysis, the Marburg I polymorphism of FSAP, which attenuates its capacity to activate prourokinase, is a significant risk predictor for the evolution and progression of carotid stenosis.
Willeit
Johann
J
Department of Neurology, University Clinics, Innsbruck, Austria. johann.willeit@uibk.ac.at
Kiechl
Stefan
S
Weimer
Thomas
T
Mair
Artur
A
Santer
Peter
P
Wiedermann
Christian J
CJ
Roemisch
Juergen
J
D000328:Adult; D000368:Aged; D016893:Carotid Stenosis / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*; D014463:Ultrasonography; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
C433550:HABP2 protein, human; D012697:Serine Endopeptidases; D014568:Urokinase-Type Plasminogen Activator