The t-PA -7351C&gt;T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid

Wolf, Anna Tjarnlund; Medcalf, Robert L.; Jern, Christina

doi:10.1182/blood-2003-12-4383

Cited by 23 publications

(40 citation statements)

References 39 publications

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“…Several in vitro studies have demonstrated this region to contain a binding site for the Sp1 transcription factor. [32][33][34] The C to T substitution at rs2020918 has been shown reduce the affinity of Sp1 to this site, suggesting a mechanism by which rs2020918 is associated with lower tPA transcription. 31,34 Our PLAT association results for the combined CVD end point replicate 2 previous studies in small samples of an association of rs2020918 with MI or stroke.…”

Section: Tissue Plasminogen Activatormentioning

confidence: 99%

“…[32][33][34] The C to T substitution at rs2020918 has been shown reduce the affinity of Sp1 to this site, suggesting a mechanism by which rs2020918 is associated with lower tPA transcription. 31,34 Our PLAT association results for the combined CVD end point replicate 2 previous studies in small samples of an association of rs2020918 with MI or stroke. In a populationbased nested case-control study (61 MI cases and 120 controls), individuals bearing the minor T allele had a significant 2.7-fold increased odds of MI compared with the CC genotype, a risk estimate similar to our finding.…”

Section: Tissue Plasminogen Activatormentioning

confidence: 99%

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

Kathiresan

Yang

Larson

et al. 2006

ATVB

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Objective-We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD). Methods and Results-In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-␤[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum Pϭ0.002) and of 7 F7 SNPs and factor VII level (minimum PϽ0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in factor VII level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global Pϭ0.0004). Conclusions-A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and factor VII level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence variation and risk of CVD. Key Words: coagulation Ⅲ fibrinogen Ⅲ genetics Ⅲ myocardial infarction Ⅲ plasminogen activators Ⅲ thrombosis Ⅲ polymorphism P lasma levels of blood clotting and fibrinolytic proteins may represent an important intermediate phenotype for cardiovascular disease (CVD) because increased circulating levels of hemostatic proteins have been associated with CVD risk. [1][2][3] Both plasma levels of hemostatic proteins 4 and occurrence of CVD 5 have a substantial heritable component. Hence, it has been suggested that sequence variation in thrombosis genes may explain interindividual variability in plasma hemostatic protein levels and CVD risk. 6 Several sequence variants at the fibrinogen-␤ (FGB) and factor VII (encoded by the F7 gene) loci have been associated consistently with circulating plasma levels of their respective gene products. [7][8][9] Previous studies have been limited by an incomplete characterization of sequence variation at these loci. The proportion of plasma protein level variation explained by cis-acting sequence variation is unclear.Recent advances in genomics allow the comprehensive evaluation of common sequence variation at a candidate gene locus for association with phenotype. Neighboring single nucleotide polymorphism (SNP) alleles are often highly correlated (ie, linkage disequilibrium [LD]). 10 Genome-wide descriptions of LD structure have been reported recently, including the International Haplotype Map (HapMap) project. 11 Within regions of LD, a subset of SNPs that are nonredundant (termed "tag SNPs") may capture the majority of common variation. 12 Thus, to test the hypothesis that common sequence variants in thrombosis...

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Section: Tissue Plasminogen Activatormentioning

confidence: 99%

Section: Tissue Plasminogen Activatormentioning

confidence: 99%

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

Kathiresan

Yang

Larson

et al. 2006

ATVB

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“…5 The mutant T allele confers a reduced transcriptional activity in vitro, and in vivo this allele is associated with reduced tPA release rates as well as increased risk of myocardial infarction (MI). [5][6][7] A recent study also reported an increased risk of ischemic stroke for the TT genotype. 8 The main inhibitor of tPA in plasma is plasminogen activator inhibitor type 1 (PAI-1), and experimental studies demonstrate that PAI-1 delays clot lysis.…”

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confidence: 99%

Fibrinolytic Gene Polymorphism and Ischemic Stroke

Jood

Ladenvall

Tjärnlund-Wolf

et al. 2005

Stroke

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Background and Purpose-The tissue-type plasminogen activator (tPA) Ϫ7351CϾT and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G Ͼ5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke. Methods-In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria. Results-There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotype combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; PϽ0.05). Plasma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was highest among those with large-vessel disease and cardioembolic stroke. Conclusions-Neither the tPA Ϫ7351CϾT nor the PAI-1 to 675 4G Ͼ5G polymorphism showed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G genotype combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compared with the heart. (Stroke. 2005;36:2077-2081.)

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“…−7351 C/T single nucleotide polymorphism of the gene encoding t-PA (rs63020761) is located within the enhancer region and the substitution of cytosine for thymine at position −7351 reduces the Sp1/Sp3 binding affinity resulting in the inhibition of DNA transcription [12]. This polymorphism was found to be strongly correlated with reduced endothelial t-PA release [13] and associated with the occurrence of myocardial infarction and stroke [14, 15].…”

Section: Introductionmentioning

confidence: 99%

The study of t-PA, u-PA and PAI-1 genes polymorphisms in patients with abdominal aortic aneurysm

Oszajca

Wroński²,

Janiszewska

et al. 2014

Mol Biol Rep

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The most important feature of abdominal aortic aneurysm (AAA) pathogenesis is an enzymatic degradation of elastic lamellae and extracellular matrix proteins particularly with participation of matrix metalloproteinases. Plasmin, which is responsible for the dissolution of fibrin in blood vessels, plays also a key role in the cascade for activation of the metalloproteinases. The purpose of this study was to evaluate the influence of selected polymorphisms in genes coding for tissue plasminogen activator (−7351 C/T polymorphism), urokinase-type plasminogen activator (1788 C/T polymorphism) and plasminogen activator inhibitor 1 (−675 4G/5G and −844 G/A polymorphism) on the susceptibility to AAA. We performed a case–control study of 153 polish patients hospitalized due to AAA and compared them with matched healthy control subjects. The polymorphisms were ascertained through genotyping by polymerase chain reaction and restriction digestion of amplified fragments or through high-resolution melting analysis. In this study we have found lower frequency of wild-type GG genotype of the −844G/A PAI-1 polymorphism in cases than in controls, what may suggest the protective effect of this genotype for the risk of AAA development. None of the remaining polymorphisms tested were associated with AAA occurrence.

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The t-PA -7351C>T enhancer polymorphism decreases Sp1 and Sp3 protein binding affinity and transcriptional responsiveness to retinoic acid

Cited by 23 publications

References 39 publications

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

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

Fibrinolytic Gene Polymorphism and Ischemic Stroke

The study of t-PA, u-PA and PAI-1 genes polymorphisms in patients with abdominal aortic aneurysm

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