Genetic Architecture of Tissue-Type Plasminogen Activator and Plasminogen Activator Inhibitor-1

Asselbergs, Folkert W.; Pattin, Kristine A.; Snieder, Harold; Hillege, Hans L.; Gilst, Wiek H. van; Moore, Jason H.

doi:10.1055/s-0028-1103367

Cited by 13 publications

(18 citation statements)

References 59 publications

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“…Heritability of PAI-1 and tPA levels in several twin studies was estimated to be 42% to 71% for PAI-1 and 43% to 62% for tPA. 10 A genome-wide meta-analysis of plasma PAI-1 levels in ;30 000 individuals 11 identified previously described variants in SERPINE1 (the PAI-1 gene) as well as novel variants in ARNTL (aryl hydrocarbon receptor nuclear translocatorlike) and PPARG (peroxisome proliferative activated receptor) that together explained up to 3.7% of the variation in PAI-1 levels. A subsequent meta-analysis of tPA levels identified variants in STXBP5 (syntaxin binding protein 5), STX2 (syntaxin 2), and PLAT (tPA) that accounted for 0.75% of the variance in tPA levels.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Ma¹,

Ozel²,

Ramdas³

et al. 2014

Blood

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• Genome-wide association analyses revealed common DNA variants in PLG, LPA, and near SIGLEC14 that contribute to plasma plasminogen level variation.• Tobacco smoking and female sex were associated with higher levels of plasminogen.Plasminogen is the precursor of the serine protease plasmin, a central enzyme of the fibrinolytic system. Plasma levels of plasminogen vary by almost 2-fold among healthy individuals, yet little is known about its heritability or genetic determinants in the general population. In order to identify genetic factors affecting the natural variation of plasminogen levels, we performed a genome-wide association study and linkage analysis in a sample of 3456 young healthy individuals who participated in the Genes and Blood Clotting Study (GABC) or the Trinity Student Study (TSS). Heritability of plasminogen levels was 48.1% to 60.0%. Tobacco smoking and female sex were associated with higher levels of plasminogen. In the meta-analysis, 11 single-nucleotide polymorphisms (SNPs) in 2 regions reached genome-wide significance (P < 5.0E-8). Of these, 9 SNPs were near the PLG or LPA genes on Chr6q26, whereas 2 were on Chr19q13 and 59 upstream of SIGLEC14. These 11 SNPs represented 4 independent signals and collectively explained 6.8% of plasminogen level variation in the study populations. The strongest association was observed for a nonsynonymous SNP in the PLG gene (R523W). Individuals bearing an additional copy of this allele had an average decrease of 13.4% in plasma plasminogen level. (Blood. 2014;124(20):3155-3164)

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Section: Introductionmentioning

confidence: 99%

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Ma¹,

Ozel²,

Ramdas³

et al. 2014

Blood

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“…21, 22 For a total of 204 SNPs, 32 SNPs within ACE, AGT, BGKRB2, PLAT, SERPINE1 have a P value <0.05 (Supplemental Table V). However, only three SNPs in PLAT (lead rs2020921, P =5.1×10 −8 ) and five SNPs in SERPINE1 (lead SNP rs2227667, P =2.2×10 −5 ) remained significant after adjusting for the multiple testing (multiple testing threshold P <2.5×10 −4 ).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

Huang¹,

Huffman²,

Yamkauchi³

et al. 2014

ATVB

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Objective Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA. Approach and Results Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke. Conclusions We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

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“…60 The PAI-1 gene is expressed in various tissues, and the endothelial cell appears as the cell type most producing circulating levels of the protein. High heritability values for the plasma levels of PAI-1 protein have been reported, ranging from 0.42 to 0.71, 61 suggesting that common variants (polymorphisms, single nucleotide polymorphisms [SNPs]) of the PAI-1 gene may play a role in the control of gene expression. About 100 polymorphisms of the PAI-1 gene have been identified, but only few of them have been investigated in P-EC and in other diseases.…”

Section: The Plasminogen Activator Inhibitor Type 1 Proteinmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Gene Polymorphisms in Pre-Eclampsia

D'Elia¹,

Fabbro²,

Driul

et al. 2011

Semin Thromb Hemost

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Pre-eclampsia (P-EC) is a multisystem disorder of pregnancy, characterized by new-onset hypertension and proteinuria. Deregulation of the coagulation cascade and hypofibrinolysis appear to play a central role in the development of this disease. After a brief review of the genetic basis of P-EC and the role of genes encoding proteins involved in coagulation, we focus on polymorphisms of the plasminogen activator inhibitor (PAI-1) gene. The most relevant association studies between PAI-1 gene polymorphisms and P-EC are reviewed. Results indicate that the 4G/4G genotype of the -675 4G/5G polymorphism represents a weak risk factor for P-EC.

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Genetic Architecture of Tissue-Type Plasminogen Activator and Plasminogen Activator Inhibitor-1

Cited by 13 publications

References 59 publications

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

Plasminogen Activator Inhibitor-1 Gene Polymorphisms in Pre-Eclampsia

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