Published online before print October 20, 2005, doi: 10.1161/01.ATV.0000191637.48129.9b
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© 2005 American Heart Association, Inc.
Thrombosis |
Genetic Variations in the Tissue Factor Gene Are Associated With Clinical Outcome in Acute Coronary Syndrome and Expression Levels in Human Monocytes
From the Divisions of Clinical Chemistry (A.M., T.T., A.S.), Cardiology (N.J., B.L., L.W.), and Molecular Medicine (T.A., A-C.S.), Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Correspondence to Agneta Siegbahn, Department of Medical Sciences, Clinical Chemistry, Uppsala University, S-751 85 Uppsala, Sweden. E-mail agneta.siegbahn{at}akademiska.se
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Abstract |
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Objective— Tissue factor (TF) has, among other factors, a prominent role in acute coronary syndrome (ACS). Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS. Moreover, we wanted to investigate the impact of associated TF SNPs on mRNA production in human monocytes.
Methods and Results— In 725 patients with ACS [Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 A>G and the –1812 C>T were genotyped among all of the FRISC-II participants (n=3143) and assessed concerning clinical outcome. Associated SNPs were genotyped in 92 healthy blood donors for comparison of TF activity and TF mRNA expression. None of the SNPs were associated with patient/control status. The 5466 A>G SNP was associated with cardiovascular death (odds ratio, 1.8; P=0.025). The CG haplotype by –1812 C>T and 5466 A>G was associated with a 3-fold increased risk of death (P<0.001). TF mRNA and basal TF activity was significantly lower among 5466 AG carriers, whereas the increase in monocyte TF activity on lipopolysaccharide stimulation was significantly stronger (P=0.04).
Conclusions— The 5466 AG genotype is a novel predictor of cardiovascular death in ACS and may act through a high TF response.
Polymorphisms in the tissue factor gene were investigated concerning association with risk and outcome in patients with acute coronary syndrome. The TF 5466 AG genotype was associated with cardiovascular death. In vitro endotoxin induced a relative increase in monocytic TF activity, which was significantly higher in AG compared with AA carriers.
Key Words: acute coronary syndrome • tissue factor • single nucleotide polymorphism • outcome • mRNA
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Introduction |
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Acute coronary syndrome (ACS) is a multifactorial disease in which a multitude of lifestyle and genetic factors contribute to the development and outcome of the disease.1 The genetic component of ACS seems to be relatively high, because family history is a strong risk factor, and heritability studies have shown a large genetic contribution to cardiac disease.2,3 Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the genome and may influence factors involved in atherosclerosis, plaque destabilization, and thrombosis, all of which are fundamental aspects of ACS etiology.3
Variations in genes that encode for hemostatic factors are considered to be likely candidates for modifiers of the procoagulant phenotype, usually observed in patients with myocardial infarction (MI).4 A procoagulant phenotype may have a substantial effect on ACS outcome, because a larger sized superimposed thrombus is directly related to the severity of myocardial ischemia.5 A major player in this respect is tissue factor (TF), which rapidly initiates blood coagulation and is generally recognized as an important thrombogenic factor in atherosclerotic lesions.6 TF is present as a membrane-bound molecule in different cell types in the vessel wall and within plaques, including endothelial cells, smooth muscle cells monocytes/macrophages, and foam cells.7 Proteolytic cleavage of TF results in a soluble form of TF (plasma TF), which only contains the extracellular part of the protein and does not show significant procoagulant activity.8 Moreover, the presence of an alternatively spliced form of TF has been reported recently.9 Intravascular TF has also been identified in shed membrane microparticles, which are potentially procoagulant, both in normal physiological conditions and under various disease conditions.10,11 It was shown recently that TF-associated microparticles have the ability to stimulate to thrombin generation and promote thrombus growth in vivo.12 Elevation of plasma TF has been observed in patients with MI and unstable angina but not in stable angina patients and healthy controls.13
The aim of the present study was to identify SNPs in the TF gene that relate to ACS. For this purpose, we measured plasma TF and genotyped 13 TF (F3 gene) SNPs in a selected group of patients (725) with ACS [Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II (FRISC-II) study] and in healthy controls (376) who were similar in age, gender, and geographic residence in Sweden. Plasma TF and SNPs were evaluated concerning death or death/MI within 6 and 24 months in the patient group and concerning differences between patients and controls. Additionally, the primarily associated SNPs were analyzed with respect to 6- and 24-month end points in the full patient group (3143 FRISC-II participants). Furthermore, TF mRNA and activity in relation to clinically associated SNPs were investigated in monocytes from 25 healthy donors.
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Methods |
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Study Populations
The patients in the present study participated in the Scandinavian multicenter FRISC-II trial.14,15 The FRISC-II study was composed of 3143 patients included in Scandinavia from 1996 to 1998 and was designed both as an intervention and a medical trial, using a factorial design. Two different settings were used to address our study aims; setting 1 (n=725) consisted of all of the patients residing in the same geographic area of Sweden as the healthy control group (n=376). Setting 1 was, thus, a sample from the FRISC-II population with a geographic match to the healthy control group. Setting 2 addressed our aim to analyze prognosis in relation to the 2 SNPs with a weak but possible association with outcome in setting 1 (5466 A>G and –1812 C>T) and consisted of all of the patients in the FRISC-II trial (3143).
Patients in FRISC-II were eligible for inclusion if they had symptoms of myocardial ischemia associated with sinus tachycardia (ST) depression (
0.1 mV), T-wave inversion (0.1 mV), or elevation of biochemical markers (creatine kinase myoglobin binding (MB) isoenzyme >6 mg/L or troponin T >0.1 mg/L). All of the patients received basic treatment with aspirin and 5 days with SC open-label dalteparin. If not contraindicated, patients were randomized within 72 hours from admission to invasive/noninvasive treatment and secondly to long-term dalteparin/placebo. Patients with contraindications to early revascularization or that were included after the official study closure were enrolled in the medical trial only, in which placebo or dalteparin treatment was administered for 90 days. The patients were followed regarding death and MI for 6 months in the medical study (3143) and for 24 months in the interventional study (2457). The details of the FRISC-II study design and patients have been described previously.14,15
The present study also included 376 healthy individuals similar in age and gender proportion. The subjects were free of self-reported illnesses and were only included if they tested normal for routine blood chemistry and electrocardiography. The healthy individuals were part of the Sweden Women and Men and Ischemic Heart Disease study.16 Both studies were previously approved by the regional ethical review board of Uppsala.
Protein Quantification
Venous blood samples were drawn into citrate tubes at the time of randomization. Blood plasma was separated by centrifugation and stored at –70°C until analysis. Plasma TF was measured using an ELISA method (American Diagnostica). The procedures for the quantification of C-reactive protein, interleukin 6, and troponin T were published previously.17
SNP Selection and Genotyping
The SNPs included in the study were chosen from the Seattle SNP or dbSNP databases.18,19 For details on the selection please see http://atvb.ahajournals.org.
For genotyping the SNPs, we used the 12-plex GenomeLab SNPStream system (Beckman Coulter) or the homogeneous template-directed dye terminator assay with fluorescence polarization detection for individual SNPs.20,21 Primer sequences are available from the authors on request. The quality of the genotype data was assessed by testing for Hardy-Weinberg equilibrium using the 
2 distribution for each assay. All of the SNPs conferred to the Hardy-Weinberg equilibrium. The overall genotype call rate was 97%, and the accuracy was 99.96% according to duplicate analysis of on average 22% of the total genotypes (4745/21 720).
TF in Mononuclear Cells
Written consent was obtained from 26 male and 66 female healthy donors (aged 20 to 61 years) for subsequent donation of EDTA blood, extraction of DNA, and determination of –1812 C>T and 5466 A>G genotypes. When samples were genotyped, all of the individuals with the –1812 CC genotype and 5466 AA or AG genotypes were asked to donate heparin blood for isolation of peripheral blood mononuclear cells and subsequent measurement of TF mRNA and activity.22,23 Please see http://atvb.ahajournals.org for details.
Data Analysis
Genotype frequency differences between patients and controls were tested by using the 2 distribution. Multiple tests were corrected for by using 1000 rounds of permutation in Haploview 3.2. Plasma TF (normally distributed) was compared between different genotypes using ANOVA with Bonferroni correction. Odds ratios for cardiovascular events were estimated using the 2 distribution with Mantel-Haenszel common odds ratio statistics. Differences regarding TF mRNA or TF procoagulant activity (PCA) were tested using the Mann–Whitney U test. Individual haplotypes were reconstructed in PHASE 2.0, and linkage disequilibrium (LD) was assessed in Haploview 3.2.24,25 Statistics for all of the data were computed in SPSS for Windows 11.5. Exact P values <0.05 were considered significant.
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Results |
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Setting 1 Patients and Healthy Controls: Risk and Outcome by SNPs and Plasma TF
Of 13 SNPs studied, neither showed association with ACS (Table I, available online at http://atvb.ahajournals.org). A weak association between the 5466 G allele and patients was observed when testing allele frequency differences without correcting for multiple tests (P=0.03; corrected P=0.21). We also observed a trend toward association between the 5466 G allele and death/MI at 6 months, which was considerably stronger if the patient was also homozygous for the –1812 C allele. None of the remaining SNPs were associated with outcome. The –1812 C>T, 1323 A>G, and 5122 C>T were in complete LD ( D’ =1.0). Strong LD ( D’ >0.7) with these variants was detected among all of the other genotyped SNPs.
Plasma TF was on average 47 pg/mL higher in patients compared with the healthy control group (P<0.001; Table 1) but were not related to gender, white blood cell count, C-reactive protein (CRP), interleukin 6 or troponin T. A comparison of plasma TF levels among all of the patients and controls revealed only 1 associated SNP; TF levels were lower among GA carriers (n=30; 2.7%) of the rare –2695 G/A SNP than among GG carriers (130 versus 168 pg/mL; corrected P=0.01).
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Elevated Levels of Plasma TF Were Not Related to Outcome
Levels of plasma TF were categorized into quartiles, and the rate of subsequent cardiac events, defined as death or MI within 6 or 24 months, was examined. There were no significant differences between the plasma TF quartiles concerning event rates (data not shown).
TF SNPs in Relation to Outcome
Setting 2 was an extension of the study in which we evaluated the possible association between the 5466 A>G SNP and outcome in all of the FRISC-II participants. Although frequencies of the –1812 C>T SNP were equal in the setting 1 patients and controls, it was genotyped also in setting 2, because this SNP is frequent, has been associated previously with TF levels, is in tight LD with several other SNPs across the TF gene, and showed a haplotype effect concerning outcome together with 5466 A>G in setting 1.26
The predefined end points investigated were death and death/MI within 6 or 24 months. The 5466 AG and GG genotypes were significantly associated with death within 24 months (Table 2; P=0.025). Event rates of death and death/MI were not significantly different between –1812 C>T genotypes. To investigate the possible haplotype risk by –1812 C>T and 5466 A>G, haplotypes were reconstructed. Three allele combinations were possible: T-A (44%), C-A (50%), and C-G (6%). Comparison of event rates between haplotypes revealed a significant increase in event rates for patients carrying the C-A/C-G haplotypes and C-G/C-G haplotypes (Table 3). Risk estimation for patients carrying either of these combinations revealed an odds ratio of 3.10 (P<0.001) for death within 24 months and 1.6 (P=0.025) for death/MI within 6 months (Table 2).
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Association of the 5466 A>G SNP with Monocytic TF mRNA Production and TF Procoagulant Activity
To follow up the clinical findings in ACS patients, we screened 92 healthy donors for the 5466 A>G and –1812 C>T SNPs. Isolation of mononuclear cells was performed at 0 and 6 months from the 14 donors who carried the –1812 CC and the 5466 AA genotype and from the 11 donors who carried the 5466 G allele (10 donors carried AG and 1 carried GG). The amount of normally spliced TF mRNA was measured in incubated controls and lipopolysaccharide (LPS)-induced cells. Alternatively spliced TF mRNA was measured in the LPS-induced samples at 0 months only.
Quantities of TF mRNAs were compared between the 5466 AA genotype and the 5466 AG or GG genotypes. The 5466 AG or GG genotype carriers had considerably lower expression of normally and alternatively spliced TF mRNA in both the incubated control and the LPS-induced samples (Figure). These experiments were repeated 6 months later with the same result (Table 4). The TF procoagulant activity, measured at 6 months only, was significantly lower in the incubated control of monocytes from 5466 AG carriers (P=0.04). However, when cells were challenged with LPS for 4 hours, AA and AG genotypes displayed similar TF activities. The relative increase in TF activity of the 5466 AG genotype was, hence, twice that of the AA genotype.
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Because both normally and alternatively spliced TF mRNA was lower among 5466 AG carriers, we investigated whether other splice variants were present in AG carriers. For experimental procedure please see http://atvb.ahajournals.org. No splice variants other than those described previously were found.
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Discussion |
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We have characterized SNPs in the TF gene in relation to risk, outcome, and plasma TF in ACS. Our main finding was that the 5466 A>G, positioned in intron 2 of the TF gene, is associated with cardiovascular death in patients with ACS. Haplotype analysis by –1812 C>T and 5466 A>G revealed the risk haplotype C-G, which increased the risk of cardiovascular death in patients with ACS by 3-fold.
TF is involved not only in the event of plaque rupture with subsequent tissue damage and after thrombosis but also in the conversion of stable plaques to unstable.27,28 Plaque destabilization by TF is likely mediated through several mechanisms, of which increased TF content in the atherosclerotic lipid core,29,30 thrombogenic potential of recruited microparticles,10and TF-FVIIa signaling promoting cell migration and neovascularization of the vessel intima31–34 may be of certain importance. Of 13 SNPs analyzed, none of the SNPs correlated with patient control status. The study had 80% power to detect a 2-fold risk increase of SNPs with a genotype frequency >10% but was not powered enough to exclude a possible risk association for more rare SNPs, whereas a correlation with plasma TF levels could be adequately evaluated, even for uncommon variants.
We observed lower levels of plasma TF in individuals with the rare –2695 A allele. However, although plasma TF was elevated among patients, no association with outcome was observed. Therefore, the significance of the relationship between ACS and –2695 G>A needs additional investigation. A possible explanation for the lack of association between plasma TF and outcome may be that both active and inactive forms of TF are recognized by this commonly used ELISA, which, therefore, does not adequately reflect thrombogenic potential or microparticle release.11 This may also explain why no effect of aspirin or statins on plasma TF was observed. Furthermore, it has been proposed that the antibody used in similar ELISA systems is not entirely specific for TF antigen and may cross-react with other proteins.35
The TF 5466 G allele was associated with death at 24 months. The C-G haplotype constructed by –1812 C>T and 5466 A>G conferred a highly increased risk of death and a moderately increased risk of death/MI at 6 months. The –1812 C>T has been studied previously in a large group of patients and controls with ACS in France and the United Kingdom. Our data agree with this study, which reported that the –1812 C>T by itself was not associated with ACS.26 However, another study reported conflicting results.36 Differences in population stratifications may be a possible explanation for the nonconcordant findings. Reny et al37 studied TF mRNA in isolated leukocytes in relation to the –1812 C>T SNP and observed significantly lower levels among CC homozygotes in unstimulated samples but not in LPS-stimulated samples. Because the –1812 C and the 5466 G alleles are linked, whereas the –1812 T and 5466 G alleles do not coexist, it is possible that this association was attributable to the 5466 G allele.
The clinical association with cardiovascular death and 5466 A>G may be partly explained by our observations in vitro with LPS-stimulated monocytes from donors carrying either the 5466 A or G allele. The G allele was associated with a lower expression of TF mRNA in unstimulated and in LPS-induced samples, whereas the TF activity was lower in the unstimulated samples only. Current evidence suggests a pool of intracellular TF, which is transported to the membrane surface on cell activation. A recent publication described the intracellular and surface distribution of monocyte TF and demonstrated individual differences in TF internalization and membrane exposure.38 In addition, a latent form of TF has been observed.39 The relative increase of TF activity on LPS stimulation for 5466 AG was twice that of 5466 AA. Thus, the lower production of TF mRNA did not reflect the TF exposure on cell membranes in the LPS-induced situation, whereas mRNA and TF activity correlated well in unstimulated samples. A likely explanation for the low TF mRNA quantities observed in 5466 AG carriers is that monocytes from this group were more readily activated, with the consequence that TF activity and mRNA expression peaked earlier and even during leukocyte isolation. One may speculate that when challenged with LPS, monocytes from 5466 AG carriers were already "exhausted" because of priming effects, and, therefore, the TF mRNA production was blunted. Indeed, in whole blood compared with isolated leukocytes, previous reports have shown opposite effects in studies of the melatonin effects on LPS stimulation, oral contraceptive effects on TF expression, and aspirin effects on TF expression.40 Thus, in the in vivo situation with monocytes in their normal environment, an early and high TF mRNA and antigen response in 5466 AG carriers may explain our clinical observations concerning this SNP.
The incomplete penetrance of the 5466 A>G and the C-G haplotype should also be commented on. Given the complex multifactorial nature of ACS, the impact on the disease by a single gene variation may not be very high, and both environmental and other genetic factors can contribute to or reduce the risk of death and MI in ACS.41 The 5466 A>G SNP was not well correlated with MI, which implies that other exogenous factors are more important than the 5466 A>G SNP in this respect. Some important factors, which may also be cofactors to the risk of mortality conferred by 5466 A>G, are other thrombogenic mechanisms, such as platelet activation with subsequent microparticle release and inflammation response on a coronary plaque rupture. Of those, platelet function may be of particular significance.
The mechanism by which the 5466 G allele influences mRNA production is yet to be determined. Possible explanations include a direct effect on transcription factor binding, the alteration of an unidentified silencer/enhancer region, or effects mediated by a functional SNP in tight LD with the 5466 A>G. Considering the normal half-life of TF mRNA at 
1.5 hours, the large differences in TF expression observed between genotypes in TF mRNA observed at 4 hours of incubation is unlikely because of changed mRNA stability.42
Some limitations of this study should be acknowledged, such as the selection bias of a nonpopulation-based sample. Thus, the most severely ill patients may not have been included in the FRISC-II study. In this context, it is noteworthy that a relatively high frequency of the C-G haplotype was observed among the 92 young and healthy donors. Another limitation is the lack of statistic power for the more rare SNPs in this study, as those would have needed a very large effect on the studied traits for association. Reversely, the lack of association of the more rare SNPs in this study may be attributable to moderate effects on studied traits and low statistical power. We chose to investigate the 5466 A>G and TF expression in isolated leukocytes to minimize background noise and to maximize TF expression levels. Testing the SNP and haplotype in whole blood, that is, the ex vivo situation, may result in a different TF expression.40
In conclusion, the 5466 A>G SNP was associated with cardiovascular death in ACS and, in combination with –1812 C>T, a highly increased risk of death and death/MI. Furthermore, the 5466 A>G SNP regulated the expression of TF mRNA in monocytes and conferred a high response of LPS-induced TF activity. These in vitro results may provide a theoretical basis for the clinical observations in our patients with ACS.
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Acknowledgments |
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This study was supported by grants from the Swedish Research Council, the Swedish Heart-Lung foundation, the Swedish Cancer foundation, the LIONS Cancer Foundation and the Josef & Linnea Carlsson Memorial Foundation. The SNP analysis of the present study was supported by the K&A Wallenberg Foundation via Wallenberg Consortium North. We thank Birgitta Fahlstrom and Annika Mylly for excellent technical assistance in ELISA management and SNP genotyping. We also thank Biostatistician Lars Berglund at Uppsala Clinical Research center for outstanding statistical expertise.
Received July 26, 2005; accepted October 5, 2005.
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References |
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|---|
1. Glass CK, Witztum JL. Atherosclerosis. The road ahead. Cell. 2001; 104: 503–516.[CrossRef][Medline] [Order article via Infotrieve]
2. Hopkins PN, Williams RR, Kuida H, Stults BM, Hunt SC, Barlow GK, Ash KO. Family history as an independent risk factor for incident coronary artery disease in a high-risk cohort in Utah. Am J Cardiol. 1988; 62: 703–707.[CrossRef][Medline] [Order article via Infotrieve]
3. Lusis AJ, Mar R, Pajukanta P. Genetics of atherosclerosis. Annu Rev Genomics Hum Genet. 2004; 5: 189–218:189–218.[CrossRef][Medline] [Order article via Infotrieve]
4. Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood. 2000; 95: 1517–1532.
5. Okamatsu K, Takano M, Sakai S, Ishibashi F, Uemura R, Takano T, Mizuno K. Elevated troponin T levels and lesion characteristics in non-ST-elevation acute coronary syndromes. Circulation. 2004; 109: 465–470.
6. Ardissino D, Merlini PA, Arlens R, Coppola R, Bramucci E, Lucreziotti S, Repetto A, Fetiveau R, Mannucci PM. Tissue factor in human coronary atherosclerotic plaques. Clin Chim Acta. 2000; 291: 235–240.[CrossRef][Medline] [Order article via Infotrieve]
7. Moons AH, Levi M, Peters RJ. Tissue factor and coronary artery disease. Cardiovasc Res. 2002; 53: 313–325.
8. Paborsky LR, Caras IW, Fisher KL, Gorman CM. Lipid association, but not the transmembrane domain, is required for tissue factor activity. Substitution of the transmembrane domain with a phosphatidylinositol anchor. J Biol Chem. 1991; 266: 21911–21916.
9. Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med. 2003; 9: 458–462.[CrossRef][Medline] [Order article via Infotrieve]
10. Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet JM, Tedgui A. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation. 2000; 101: 841–843.
11. Aras O, Shet A, Bach RR, Hysjulien JL, Slungaard A, Hebbel RP, Escolar G, Jilma B, Key NS. Induction of microparticle- and cell-associated intravascular tissue factor in human endotoxemia. Blood. 2004; 103: 4545–4553.
12. Biro E, Sturk-Maquelin KN, Vogel GM, Meuleman DG, Smit MJ, Hack CE, Sturk A, Nieuwland R. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost. 2003; 1: 2561–2568.[CrossRef][Medline] [Order article via Infotrieve]
13. Suefuji H, Ogawa H, Yasue H, Kaikita K, Soejima H, Motoyama T, Mizuno Y, Oshima S, Saito T, Tsuji I, Kumeda K, Kamikubo Y, Nakamura S. Increased plasma tissue factor levels in acute myocardial infarction. Am Heart J. 1997; 134: 253–259.[CrossRef][Medline] [Order article via Infotrieve]
14. Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease. Lancet. 1999; 354: 701–707.[CrossRef][Medline] [Order article via Infotrieve]
15. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease. Lancet. 1999; 354: 708–715.[CrossRef][Medline] [Order article via Infotrieve]
16. Johnston N, Jernberg T, Lindahl B, Lindback J, Stridsberg M, Larsson A, Venge P, Wallentin L. Biochemical indicators of cardiac and renal function in a healthy elderly population. Clin Biochem. 2004; 37: 210–216.[CrossRef][Medline] [Order article via Infotrieve]
17. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA. 2001; 286: 2107–2113.
18. SeattleSNPs. NHLBI Program for Genomic Applications, UW-FHCRC, Seattle, WA. Available at: http://pga.gs.washington.edu/. Accessed November 2003.
19. NIH dbSNP database. Available at: http://www.ncbi.nlm.nih.gov/SNP/. Accessed November 2003.
20. Bell PA, Chaturvedi S, Gelfand CA, Huang CY, Kochersperger M, Kopla R, Modica F, Pohl M, Varde S, Zhao R, Zhao X, Boyce-Jacino MT, Yassen A. SNPstream UHT: ultra-high throughput SNP genotyping for pharmacogenomics and drug discovery. Biotechniques. 2002; Suppl: 70–2, 74, 76–7:70–77.
21. Hsu TM, Chen X, Duan S, Miller RD, Kwok PY. Universal SNP genotyping assay with fluorescence polarization detection. Biotechniques. 2001; 31: 560,562, 564-560,8, passim.[Medline] [Order article via Infotrieve]
22. Lindmark E, Tenno T, Chen J, Siegbahn A. IL-10 inhibits LPS-induced human monocyte tissue factor expression in whole blood. Br J Haematol. 1998; 102: 597–604.[CrossRef][Medline] [Order article via Infotrieve]
23. Malarstig A, Tenno T, Jossan S, Aberg M, Siegbahn A. A quantitative real-time PCR method for tissue factor mRNA. Thromb Res. 2003; 112: 175–183.[CrossRef][Medline] [Order article via Infotrieve]
24. Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003; 73: 1162–1169.[CrossRef][Medline] [Order article via Infotrieve]
25. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21: 263–265.
26. Arnaud E, Barbalat V, Nicaud V, Cambien F, Evans A, Morrison C, Arveiler D, Luc G, Ruidavets JB, Emmerich J, Fiessinger JN, Aiach M. Polymorphisms in the 5' regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism: the ECTIM and PATHROS studies. Etude Cas-Temoins de l’Infarctus du Myocarde. Paris Thrombosis case-control Study. Arterioscler Thromb Vasc Biol. 2000; 20: 892–898.
27. Jander S, Sitzer M, Wendt A, Schroeter M, Buchkremer M, Siebler M, Muller W, Sandmann W, Stoll G. Expression of tissue factor in high-grade carotid artery stenosis: association with plaque destabilization. Stroke. 2001; 32: 850–854.
28. Annex BH, Denning SM, Channon KM, Sketch MH Jr, Stack RS, Morrissey JH, Peters KG. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation. 1995; 91: 619–622.
29. Tremoli E, Camera M, Toschi V, Colli S. Tissue factor in atherosclerosis. Atherosclerosis. 1999; 144: 273–283.[CrossRef][Medline] [Order article via Infotrieve]
30. Corti R, Hutter R, Badimon JJ, Fuster V. Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis. J Thromb Thrombolysis. 2004; 17: 35–44.[CrossRef][Medline] [Order article via Infotrieve]
31. Siegbahn A, Johnell M, Rorsman C, Ezban M, Heldin CH, Ronnstrand L. Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis. Blood. 2000; 96: 3452–3458.
32. Kumamoto M, Nakashima Y, Sueishi K. Intimal neovascularization in human coronary atherosclerosis: its origin and pathophysiological significance. Hum Pathol. 1995; 26: 450–456.[CrossRef][Medline] [Order article via Infotrieve]
33. Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A, Carmeliet P, Mueller BM, Friedlander M, Ruf W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med. 2004; 10: 502–509.[CrossRef][Medline] [Order article via Infotrieve]
34. Siegbahn A, Johnell M, Sorensen BB, Petersen LC, Heldin CH. Regulation of chemotaxis by the cytoplasmic domain of tissue factor. Thromb Haemost. 2005; 93: 27–34.[Medline] [Order article via Infotrieve]
35. Butenas S, Bouchard BA, Brummel-Ziedins KE, Parhami-Seren B, Mann KG. Tissue factor activity in whole blood. Blood. 2005; 105: 2764–2770.
36. Ott I, Koch W, von Beckerath N, de Waha R, Malawaniec A, Mehilli J, Schomig A, Kastrati A. Tissue factor promotor polymorphism -603 A/G is associated with myocardial infarction. Atherosclerosis. 2004; 177: 189–191.[CrossRef][Medline] [Order article via Infotrieve]
37. Reny JL, Laurendeau I, Fontana P, Bieche I, Dupont A, Remones V, Emmerich J, Vidaud M, Aiach M, Gaussem P. The TF-603A/G gene promoter polymorphism and circulating monocyte tissue factor gene expression in healthy volunteers. Thromb Haemost. 2004; 91: 248–254.[Medline] [Order article via Infotrieve]
38. Egorina EM, Sovershaev MA, Bjorkoy G, Gruber FX, Olsen JO, Parhami-Seren B, Mann KG, Osterud B. Intracellular and surface distribution of monocyte tissue factor: application to intersubject variability. Arterioscler Thromb Vasc Biol. 2005; 25: 1493–1498.
39. Osterud B. The role of platelets in decrypting monocyte tissue factor. Dis Mon. 2003; 49: 7–13.[Medline] [Order article via Infotrieve]
40. Osterud B. Tissue factor expression in monocytes: in vitro compared to ex vivo. Thromb Haemost. 2000; 84: 521–522.[Medline] [Order article via Infotrieve]
41. Terwilliger JD, Haghighi F, Hiekkalinna TS, Goring HH. A bias-ed assessment of the use of SNPs in human complex traits. Curr Opin Genet Dev. 2002; 12: 726–734.[CrossRef][Medline] [Order article via Infotrieve]
42. Gregory SA, Morrissey JH, Edgington TS. Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol. 1989; 9: 2752–2755.
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 L. Jiang, C. Y. Liu, Q. F. Yang, P. Wang, and W. Zhang Plasma Level of Growth Arrest-Specific 6 (GAS6) Protein and Genetic Variations in the GAS6 Gene in Patients With Acute Coronary Syndrome Am J Clin Pathol, May 1, 2009; 131(5): 738 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Malarstig, P Eriksson, A Hamsten, B Lindahl, L Wallentin, and A Siegbahn Raised interleukin-10 is an indicator of poor outcome and enhanced systemic inflammation in patients with acute coronary syndrome Heart, June 1, 2008; 94(6): 724 - 729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Campo, M. Valgimigli, P. Ferraresi, P. Malagutti, M. Baroni, C. Arcozzi, D. Gemmati, G. Percoco, G. Parrinello, R. Ferrari, et al. Tissue Factor and Coagulation Factor VII Levels During Acute Myocardial Infarction: Association With Genotype and Adverse Events Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2800 - 2806. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steffel, T. F. Luscher, and F. C. Tanner Tissue Factor in Cardiovascular Diseases: Molecular Mechanisms and Clinical Implications Circulation, February 7, 2006; 113(5): 722 - 731. [Abstract] [Full Text] [PDF]
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