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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A high level of plasma fibrinogen has been shown to be an important risk factor for myocardial infarction and stroke. Thus, we were prompted to investigate regulation of human fibrinogen biosynthesis, a process wherein expression of the B beta-chain of fibrinogen appears to be rate-limiting for fibrinogen secretion. Using electrophoretic mobility shift assays with synthetic probes representing portions of the human B beta-fibrinogen promoter, we have defined several elements that bind distinct classes of transcription factors present in human hepatoma cell nuclear extracts. The contribution of each element to promoter activity was demonstrated in transfection experiments using promoter-chloramphenicol acetyltransferase constructs and human hepatoma cells. Our observations indicate that two distinct sequence elements are required for maximal induction of transcription by interleukin-6. One of these sequences is an IL-6-RE core element similar to that reported for the rat alpha 2-macroglobulin promoter and the other is a binding site for the C/EBP family of transcription factors. We also report two additional elements, one negative- and one positive-acting, that bind novel sequence-specific factors.
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PMID:Functional characterization of promoter elements involved in regulation of human B beta-fibrinogen expression. Evidence for binding of novel activator and repressor proteins. 822 73

The relationship between the apolipoprotein E (apoE) and beta-fibrinogen G/A-455 polymorphisms and cerebrovascular disease (CVD) was examined in the present study. We compared 227 patients with the subtypes of CVD (large-vessel disease, lacunar stroke, cardiac embolism, or undetermined pathomechanisms) with 225 control subjects. The occurrence of apoE isoforms (E2, E3, and E4) and the beta-fibrinogen G/A-455 genotype was determined in these individuals. No differences in apoE polymorphisms or allele frequencies between the CVD patients and control subjects were found. However, analysis of apoE genotypes as a function of stroke subtype revealed that the apoE4 allele was significantly more common in those patients with macroangiopathy-associated CVD. The only CVD risk factor that distinguished patients with the E4 allele from those with other apoE genotypes was elevated cholesterol. No association between the beta-fibrinogen G/A-455 polymorphism and CVD was found. However, homozygosity for the A allele was more common in patients with CVD resulting from large-vessel disease. These data demonstrate that the apoE4 allele and the AA genotype of the beta-fibrinogen G/A-455 polymorphism occur significantly more frequently in patients with CVD resulting from stenosis of large, brain-supplying vessels. Such genetic analyses may further our understanding of the etiology of cerebrovascular disease.
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PMID:The apolipoprotein E and beta-fibrinogen G/A-455 gene polymorphisms are associated with ischemic stroke involving large-vessel disease. 940 70

Plasma fibrinogen is a major risk factor for coronary heart disease, stroke, and peripheral artery disease. There is evidence that genetic variation in the beta-fibrinogen gene contributes to the rate of synthesis of fibrinogen, but the molecular mechanism underlying the genetic heritability of the plasma fibrinogen concentration is largely unknown. We evaluated the physiological roles of 5 common nucleotide substitutions in the promoter region of the beta-fibrinogen gene at positions -148, -249, -455, -854, and -993 from the transcriptional start site. Electrophoretic mobility shift assays revealed distinct differences in the binding characteristics of nuclear proteins between wild-type and mutant fragments of both the -455G/A and -854G/A polymorphisms, whereas no clear differences were observed for the -148C/T, -249C/T, and -993C/T sites. Transfection studies in HepG2 cells showed increased basal rates of transcription for both the G-to-A substitution at position -455 (+50%, P<0.05) and the G-to-A substitution at -854 (+51%, P<0.05). Additional transfection studies using proximal promoter constructs confirmed that both the -455A and -854A alleles independently enhance the basal rate of transcription of the beta-fibrinogen gene. The rare alleles of the nonrelated -455G/A and -854G/A polymorphisms were also associated with significantly increased plasma fibrinogen levels in healthy middle-aged men. Overall, the 2 polymorphisms together explained approximately 11% of the variation in plasma fibrinogen concentration. It is concluded that the -455G/A and -854G/A polymorphisms of the beta-fibrinogen gene are physiologically relevant mutations with a significant impact on the plasma fibrinogen concentration.
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PMID:Two common, functional polymorphisms in the promoter region of the beta-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. 1059 88

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIbalpha; platelet ligands beta-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and P-selectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P = 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone (chi(2) = 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P = 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.
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PMID:The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. 1208 90

In large prospective studies, plasma fibrinogen levels have been shown to be an independent risk factor of vascular disease, including ischemic stroke. Elevated plasma fibrinogen in an individual could be due to the presence of predisposing genetic and/or environmental factors, such as smoking. Of the polymorphisms studies to date, the beta-fibrinogen-455 (beta-Fg-455) G-->A substitution in the 5' flanking region is associated with the most consistent difference in plasma fibrinogen levels in both case-control studies and in selected groups of healthy individuals. In order to further elucidate the role of the beta-Fg-455 G-->A substitution in determining fibrinogen levels and susceptibility to ischemic stroke in case-control population, including 104 individuals with verified ischemic stroke and 156 healthy individuals. Turbidimetriy assays were used to measure plasma fibrinogen levels of all samples. The beta-Fg-455 G-->A mutation was identified by the polymerase chain reaction followed by restriction enzyme digestion of the amplified DNA with HaeIII. The plasma fibrinogen level in patients with ischemic stroke [(3.51 +/- 1.09) g/L] was significantly higher than that in the control [(3.08 +/- 0.71) g/L] (P < 0.01). The A-allele is associated with elevated fibrinogen levels in both patients and controls. The plasma fibrinogen levels in controls with A-allele in elder people were higher than in younger people (P < 0.05). Those with A allele in males of ischemic stroke had significantly higher plasma fibrinogen levels in smokers than in non-smokers and ex-smokers (P < 0.05), but it was not significantly difference in subjects of GG genotype (P > 0.05). Our data demonstrates an association of the beta-Fg promoter A-455 allele with higher fibrinogen levels in the general population, and suggests that the A-allele may be a susceptible predictor of ischemic stroke, particularly in aging and smoking.
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PMID:[Effect of beta-Fibrinogen-455 Gene Polymorphism on Plasma Fibrinogen Levels in Patients with Ischemic Stroke] 1257 26

The role of genetic factors in the individual predisposition to develop ischemic stroke has been assessed by previous studies performed both in animal models and in humans. The main goal of the current investigation was to determine the possible contribution of genes encoding procoagulant and inflammatory factors on the occurrence of ischemic stroke in a cohort of young cases and corresponding controls. One hundred and fifteen cases of ischemic stroke were recruited for this study. A detailed clinical assessment, a definite etiologic diagnosis, as well as the presence/absence of known risk factors for ischemic stroke were obtained for each patient. As a control group 180 healthy, unrelated subjects were included. The whole population was screened for polymorphisms belonging to genes encoding FII, FV, alpha-fibrinogen, beta-fibrinogen, GP IIb/IIIa, tumor necrosis factor (TNF)-alpha, interleukin 1-beta. Hypertension was the most important risk factor for ischemic stroke in our cohort [OR = 6.9, confidence interval (CI) 2.9-16.7, P < 0.0001]. Among all genes tested, the TNF-alpha gene variant exerted a significant, independent effect on individual predisposition to ischemic stroke occurrence (OR = 1.8, CI = 1.01-3.3, P < 0.05). Our findings, obtained in a cohort of young Italian patients, may support the existence of a direct contributory role of TNF-alpha, a proinflammatory cytokine protein, in the susceptibility to brain damage.
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PMID:A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study. 1632 93

We examined an association of the C-148T beta-fibrinogen gene polymorphism with fibrinogen level and platelet aggregation in patients with ischemic stroke and in people with vascular risk factors but no ischemic stroke. Among stroke patients, carriers of an -148T allele had significantly higher plasma fibrinogen level and platelet aggregation to norepinephrin compared to the C/C homozygotes. No significant differences in frequencies of a C-148 allele between stroke patients and controls were observed.
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PMID:[The beta-fibrinogen gene polymorphism, fibrinogen level and platelet aggregation in patients with ischemic stroke]. 1943 Dec 72

Elevated plasma fibrinogen levels have been identified as an independent risk factor for coronary heart diseases, stroke and peripheral artery disease. The -455G/A polymorphism in the promoter region of the beta-fibrinogen gene has been associated with increased plasma fibrinogen levels. However, the functional effect of this polymorphism has been controversial and other polymorphisms in the fibrinogen gene have also been implicated in higher fibrinogen levels. In this study, we evaluated the transcriptional activity of 4 natural haplotypes and 6 artificial haplotypes in the promoter region of the beta-fibrinogen gene. Significantly lower IL-6-induced activity was observed in the -1420A and -148T alleles. In contrast, the -854A allele had significantly higher activity. Artificial haplotypes containing the -1420A, -854A and -148T alleles were also analyzed to confirm individual functional effects. The -1420A and -148T alleles significantly lowered the activities, while the -854A allele significantly raised the activity. From this study we conclude that the -1420G/A, -854G/A and -148C/T polymorphisms in the beta-fibrinogen promoter region are functional polymorphisms while the -455G/A polymorphism may not be a functional one, and that the association of the -455G/A polymorphism with higher fibrinogen levels may actually be due to linkage disequilibrium between the -455G/A polymorphism and other truly functional polymorphisms.
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PMID:The functional effects of the -455G/A polymorphism on the IL-6-induced expression of the beta-fibrinogen gene may be due to linkage disequilibrium with other functional polymorphisms. 1981 41