Factor VII Activating Protease Polymorphism (G534E) Is Associated with Increased Risk for Stroke and Mortality

Abstract

Introduction. The FSAP-Marburg I polymorphism (1704G > A), which reduces FSAP activity, is associated with late complications of carotid stenosis in humans. Therefore, this study examines the influence of the Marburg I polymorphism and the closely linked Marburg II polymorphism (1280G > C) on various cardiovascular outcomes in two large independent study populations. Methods. The two Marburg polymorphisms in the HABP2 gene encoding FSAP were genotyped in a large population of elderly patients at risk for vascular disease (the PROSPER-study, n = 5804) and in a study population treated with a percutaneous coronary intervention (the GENDER-study, n = 3104). Results. In the PROSPER study, the Marburg I polymorphism was associated with an increased risk of clinical stroke (HR: 1.60, 95% CI: 1.13–2.28) and all-cause mortality (HR: 1.33, 95% CI: 1.04–1.71). In the GENDER study carriers of this variant seemed at lower risk of developing restenosis (HR: 0.59, 95% CI: 0.34–1.01). The Marburg II polymorphism showed similar but weaker results. Conclusion. The increase in stroke risk in Marburg I carriers could be due to differential effects on smooth muscle cells and on matrix metalloproteinases, thereby influencing plaque stability. The possible protective effect on restenosis could be the result of reduced activation of zymogens, which are involved in hemostasis and matrix remodeling.

Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells

“…In a large correlation study of stroke patients, MI was found to increase the risk for stroke and mortality 69 and increased FSAP activity and antigen levels were found in ischemic stroke patients 70 . Furthermore low FSAP antigen level was associated with recanalization in stroke patients after tPA treatment 71 .…”

Factor VII-Activating Protease Is Activated in Multiple Trauma Patients and Generates Anaphylatoxin C5a

“…A single nucleotide polymorphism (SNP) in the FSAP gene (Marburg I [MI] SNP, G534E, 1601G/A) results in a protein with reduced enzymatic activity (9). Moreover, the MI-SNP was found to be strongly linked to carotid stenosis (10), cardiovascular disease in general (11), stroke and its related mortality (12), and plaque thickness and calcification (13,14). Recent studies show that FSAP zymogen in plasma can be activated by histones and nucleosomes arising from necrotic and/or apoptotic cells (15,16).…”

Circulating Factor VII Activating Protease (FSAP) Is Associated With Clinical Outcome in Acute Coronary Syndrome

“…13 The protease expressed by the FSAP gene carrying the single nucleotide polymorphism (SNP) Marburg I (MI; G534E, 1601 G/A) has a reduced ability to activate pro-uPA and FVII, and inactivate TFPI. 12, 14 The MI-SNP was found to be an independent risk factor for the development of late complications of carotid stenosis 15 and may also be related to the occurrence of venous thromboembolism 16 and is associated with increased risk for stroke, 17 thus representing a general cardiovascular risk factor. 18 Recently, the measurement of circulating FSAP antigen and activity demonstrated a modest association between elevated FSAP concentration and venous thromboembolism.…”

“…12 More recently, various studies have supported the emerging role of FSAP in advanced atherosclerosis and cardiovascular diseases. [13][14][15][16][17] Next to hepatocytes, the major cellular source of intravascular FSAP is monocytes, the only blood cells capable of synthesizing FSAP in response to various inflammatory mediators such as cytokines and bacterial endotoxins. 13 FSAP expression is also enhanced by differentiation of human circulating monocytes into macrophages.…”