The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke. A case-control study.

High levels of plasminogen activator inhibitor type 1 (PAI-1) have been implicated as a risk factor for cardiovascular disease, but its precise role remains controversial. The 4G allele of the PAI-1 4G/5G promoter polymorphism is associated with higher levels of PAI-1. We studied the relationship between ischemic stroke and the PAI-1 4G/5G polymorphism and PAI-1 antigen levels. We performed a case-control study among patients aged 18-75 years with first ischemic stroke, confirmed by CT. All patients were screened for cardiovascular risk factors, cardiac disorders and large vessel disease. We excluded patients with a definite non-atherosclerotic cause of the stroke and patients using oral anticoagulants. Population-controls were age -and sex-matched, without a history of stroke, and of the Caucasian race. Venous blood samples were taken for PAI-1 4G/5G polymorphism and PAI-1 level one week after stroke. We included 124 patients and 125 controls. Mean age was 56 yrs (range 18 to 75 yrs). Sixty one patients (50%) and 58 (47%) controls were heterozygous for the PAI-1 4G/5G polymorphism. The homozygous 4G/4G genotype was found in 33 patients (27%) and in 36 controls (29%). The odds ratio of ischemic stroke associated with 4G-carriers versus 5G/5G homozygotes was 1.0 (95% CI: 0.6-1.8). The relative risk of ischemic stroke associated with the level of PAI-1 in the upper quartile was 0.73 (95%CI: 0.4 to 1.4). Neither the PAI-1 4G/5G polymorphism nor the PAI-1 antigen level is a strong risk factor for ischemic stroke.

Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris.

Decrease of fibrinolytic potential is considered to be a risk factor for arterial thrombosis. The recently described thrombin-activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis by cleaving of the C-terminal lysine residues from fibrin, thereby inhibiting tPA mediated plasminogen activation. The role of plasma TAFI antigen (Ag) levels and gene polymorphisms in arterial thrombosis is still not elucidated. In this prospective study, the association between plasma TAFI Ag levels and the TAFI gene polymorphisms, Ala147Thr, Thr325Ile and -438A/G, with refractory unstable angina pectoris (UAP) was determined. The study population consisted of 209 patients with UAP of whom 76 were refractory and 133 non-refractory to medical treatment. In the same study population the contribution of these polymorphisms to plasma TAFI Ag levels was determined. Plasma TAFI Ag levels were significantly higher in non-refractory patients compared to refractory patients (geometric mean 114.4 and 105.6 U/dl respectively, p=0.042). Plasma TAFI Ag levels in the lowest quartile resulted in a 2.6 fold (95% confidence interval 1.2-5.9) increased risk for refractory UAP compared to plasma TAFI Ag levels in the upper quartile. The three studied TAFI polymorphisms had an independent and additive effect on plasma TAFI Ag levels. However, no significant association between the individual TAFI polymorphisms and refractiveness was observed. In conclusion, in this study population plasma TAFI Ag levels are significantly correlated with refractiveness in patients with UAP. Furthermore, all three polymorphisms contribute independently to plasma TAFI Ag levels, but not to refractiveness.

PLA1/A2 polymorphism of the platelet glycoprotein receptor IIb/IIIa in young patients with cryptogenic TIA or ischemic stroke.

BACKGROUND: The relationship between the PIA2 allele of the Leu(33)Pro polymorphism of glycoprotein IIb/IIIa receptor (GPIIb/IIIa) and ischemic stroke is uncertain. The purpose of this study was to investigate a possible association between the GPIIb/IIIa PIA1/A2 polymorphism and the occurrence of cryptogenic stroke in young patients. METHODS: From a consecutive series of 80 patients aged 45 or less with a recent ischemic stroke or TIA, we selected 45 patients with stroke due to small vessel occlusion or stroke of undetermined etiology (according to the TOAST criteria). Controls were 60 healthy blood donors with a similar age distribution. All patients underwent CT of the brain and were screened for cardiovascular risk factors, cardiac disorders and large vessel disease. The frequency of the PIA2 allele was determined by PCR and Msp1 restriction analysis. RESULTS: Eight patients (16%) and 16 controls (27%) were heterozygous for PIA2 allele. Two patients (4%) were homozygous for PIA2. The relative risk of ischemic stroke associated with PIA2 allele was estimated at 0.8 (95% CI: 0.3-1.9). CONCLUSION: This study does not support the association between the PIA1/A2 polymorphism and cryptogenic stroke or TIA in patients aged 45 or less.

Identification of a novel Gsp-related pathway required for secretion of the manganese-oxidizing factor of Pseudomonas putida strain GB-1.

The manganese-oxidizing factor of Pseudomonas putida strain GB-1 is associated with the outer membrane. One of the systems of protein transport across the outer membrane is the general secretory pathway (Gsp). The gsp genes are called xcp in Pseudomonas species. In a previous study, it was shown that mutation of the prepilin peptidase XcpA and of a homologue of the pseudopilin XcpT inhibited transport of the factor. In the present study, we describe the genomic region flanking the xcpT homologue (designated xcmT1). We show that xcmT1 is part of a two-gene operon that includes an xcpS homologue (designated xcmS). No other xcp-like genes are present in the regions flanking the xcmT1/xcmS cluster. We also characterized the site of transposon insertion of another transport mutant of P. putida GB-1. This insertion appeared to be located in a gene (designated xcmX) possibly encoding another pseudopilin-related protein. This xcmX is clustered with two other xcpT-related genes (designated xcmT2 and xcmT3) on one side and homologues of three csg genes (designated csmE, csmF and csmG) on the other side. The csg genes are involved in production of aggregative fibres in Escherichia coli and Salmonella typhimurium. A search for XcmX homologues revealed that the recently published genome of Ralstonia solanacearum and the unannotated genome of P. putida KT2440 contain comparable gene clusters with xcmX and xcp homologues that are different from the well-described 'regular'xcp/gsp clusters. They do contain xcpR and xcpQ homologues but, for example, homologues of xcpP, Y and Z are lacking. The results suggest a novel Xcp-related system for the transport of manganese-oxidizing enzymes to the cell surface.

Genetic variability of von Willebrand factor and risk of coronary heart disease: the Rotterdam Study.

The von Willebrand factor (VWF) may be causally associated with coronary heart disease (CHD) or merely be a marker of endothelial damage. The G allele of the -1793 C/G promoter polymorphism in the VWF gene has been associated with higher plasma levels of VWF. To investigate whether VWF has a causal role in CHD, we designed a case-cohort study, including 352 subjects with CHD and a random cohort (n = 736), and prospectively examined the association of the -1793 C/G polymorphism with CHD in subjects with and without advanced atherosclerosis. All subjects were