Common Genetic Variation in Five Thrombosis Genes and Relations to Plasma Hemostatic Protein Level and Cardiovascular Disease Risk

Kathiresan, Sekar; Yang, Qiong; Larson, Martin G.; Camargo, Amy L.; Tofler, Geoffrey H.; Hirschhorn, Joel N.; Gabriel, Stacey; O’Donnell, Christopher J.

doi:10.1161/01.atv.0000222011.13026.25

Cited by 61 publications

(53 citation statements)

References 38 publications

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“…In line with this hypothesis, it has been found that subjects carrying a variant of the t-PA gene with a low capacity for t-PA release are at greater risk of suffering a MI [4,5]. This finding was recently reproduced in the Framingham cohort [6]. A reduced capacity to release t-PA has also been observed in subjects with an increased risk of myocardial infarction, i.e.…”

Section: Introductionmentioning

confidence: 84%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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Section: Introductionmentioning

confidence: 84%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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“…Fibrinogen gene variation and ischemic stroke 901 associated with increased plasma fibrinogen level [20][21][22]30]. The effect was modest and only present in cases.…”

Section: Discussionmentioning

confidence: 99%

“…Results indicate that the FGA and FGG genes may be of importance [13,14]. In contrast, several studies have investigated the possible association between fibrinogen gene polymorphisms, plasma fibrinogen level, and ischemic stroke, as well as coronary heart disease [15][16][17][18][19][20][21][22]. Although many studies have reported an association between FGB gene polymorphism and plasma fibrinogen, results have been inconsistent with respect to cardiovascular and cerebrovascular events [22].…”

Section: Introductionmentioning

confidence: 99%

Fibrinogen gene variation and ischemic stroke

Jood

Danielson

Ladenvall

et al. 2008

Journal of Thrombosis and Haemostasis

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Summary. Background: Plasma fibrinogen level and fibrin clot structure are heritable traits that may be of importance in the pathogenesis of ischemic stroke. Objectives: To investigate associations between variation in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes, fibrinogen level, and ischemic stroke. Methods: The Sahlgrenska Academy Study on Ischemic Stroke comprises 600 cases and 600 matched population controls. Stroke subtypes were defined according to TOAST criteria. Plasma fibrinogen level was measured by an automated clot-rate assay. Eight tagging single nucleotide polymorphisms (SNPs) were selected to capture genetic variation in the FGA, FGG, and FGB genes. Results: Plasma fibrinogen was independently associated with overall ischemic stroke and all subtypes, both in the acute stage (P < 0.001) and at three-month follow-up (P < 0.05). SNPs belonged to two haplotype blocks, one containing the FGB gene and the other the FGG and FGA genes. FGB haplotypes were associated with fibrinogen level (P < 0.01), but not with ischemic stroke. In contrast, FGG/FGA haplotypes showed independent association to ischemic stroke but not to fibrinogen level. In an additive model with the most common FGG/FGA haplotype (A1) as reference, the adjusted odds ratios of ischemic stroke were 1.4 [95% confidence interval (95% CI) 1.1-1.8], P < 0.01, 1.4 (95% CI 1.0-1.8), P < 0.05, and 1.5 (95% CI 1.0-2.1), P < 0.05 for the A2, A3, and A4 FGG/FGA haplotypes, respectively. Conclusion: FGG/FGA haplotypes show association to ischemic stroke. This association is independent of fibrinogen level, thus suggesting that the association between ischemic stroke and variation at the FGG/FGA genes is mediated by qualitative rather than quantitative effects on fibrin(ogen).

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“…Recent progress in genomics, such as the International HapMap Project [International HapMap Consortium, 2005] allows the comprehensive study of common sequence variation at a gene locus, and the identification of blocks of linkage disequilibrium (LD) for neighboring SNPs. In the fibrinogen gene cluster, 44 SNPs spanning a genomic region of 61.8 kb were found to fall into three LD blocks, with four to six haplotypes for each block, representing more than 95% of chromosomes [Kathiresan et al, 2006].…”

Section: Polymorphismsmentioning

confidence: 99%

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Neerman-Arbez

Moerloose

2007

Hum. Mutat.

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Communicated by Arupa GangulyFibrinogen is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aa, Bb, and c). Each polypeptide is encoded by a distinct gene, FGA, FGB, and FGG, all three clustered in a region of 50 kb on 4q31. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Although the disease was first described in 1920, the genetic defect responsible for this disorder long remained unknown. We identified the gene and the first causative mutations for this disease in a nonconsanguineous Swiss family in 1999. Since this first report, 61 additional mutations, the majority in FGA, have been identified in patients with afibrinogenemia (in homozygosity or in compound heterozygosity) or in heterozygosity in hypofibrinogenemia, since many of these patients are in fact asymptomatic carriers of afibrinogenemia mutations. Mutations in the fibrinogen genes may lead to deficiency of fibrinogen by several mechanisms: these can act at the DNA level, at the RNA level by affecting mRNA splicing or stability, or at the protein level by affecting protein synthesis, assembly, or secretion. The expression of selected mutations has shown that mechanisms acting at all three levels play a role in the molecular basis of this disease. We report here the identification of 10 novel mutations, of which eight are localized in FGA, thus increasing the total number of causative mutations identified to 72 and confirming the relative importance of FGA in the molecular basis of fibrinogen deficiency. Hum Mutat 28(6), [540][541][542][543][544][545][546][547][548][549][550][551][552][553] 2007. r r 2007 Wiley-Liss, Inc.

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Common Genetic Variation in Five Thrombosis Genes and Relations to Plasma Hemostatic Protein Level and Cardiovascular Disease Risk

Cited by 61 publications

References 38 publications

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Fibrinogen gene variation and ischemic stroke

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

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