Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis

Argirios E. Tsantes; Georgios K. Nikolopoulos; Pantelis G. Bagos; Evdoxia Rapti; Georgios Mantzios; Violeta Kapsimali; Anthi Travlou

doi:10.1160/TH06-12-0745

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(06): 907-913
DOI: 10.1160/TH06-12-0745

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis

A meta-analysis

Argirios E. Tsantes

¹Laboratory of Hematology & Blood Bank Unit, 'Attikon' General Hospital, School of Medicine, University of Athens, Athens, Greece

,

Georgios K. Nikolopoulos

²Hellenic Centre for Disease Control and Prevention, Athens, Greece

,

Pantelis G. Bagos

³Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, Greece

,

Evdoxia Rapti

¹Laboratory of Hematology & Blood Bank Unit, 'Attikon' General Hospital, School of Medicine, University of Athens, Athens, Greece

,

Georgios Mantzios

¹Laboratory of Hematology & Blood Bank Unit, 'Attikon' General Hospital, School of Medicine, University of Athens, Athens, Greece

,

Violeta Kapsimali

⁴Immunology-Histocompatibility Department, Evangelismos Hospital, Athens, Greece

,

Anthi Travlou

¹Laboratory of Hematology & Blood Bank Unit, 'Attikon' General Hospital, School of Medicine, University of Athens, Athens, Greece

› Author Affiliations

Abstract

Summary

The effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068–1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR:1.833,95% CI:1.325–2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.

Keywords

venous thromboembolism - PAI-1 - 4G/5G genetic polymorphism

Full Text

References

References
1 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-387.
2 Dawson S, Wiman B, Hamsten A. et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-10745.
3 Eriksson P, Kallin B, van’t Hooft FM. et al. Allelespecific increase in basal transcription of the plasmiogen activator inhibitor 1 gene is associated with myocardial infarction. Proc Nat Acad Sci USA 1995; 92: 1851-1855.
4 Ye Z, Liu EHC, Higgins JPT. et al. Seven haemostatic gene polymorphisms in coronary disease: metaanalysis of 66,155 cases and 91,307 controls. Lancet 2006; 367: 651-658.
5 Hoekstra T, Geleijnse JM, Schouten EG. et al. Plasminogen activator inhibitor – type 1: its plasma determinants and relation with cardiovascular risk. Thromb Haemost 2004; 91: 861-872.
6 Grubic N, Stegnar M, Peternel P. et al. A novel G/A and the 4G/5G polymorphism within the promoter of the plasminogen activator inhibitor –1 gene in patients with deep vein thrombosis. Thromb Res 1996; 84: 431-443.
7 Ridker PM, Hennekens CH, Lindpainter K. et al. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1997; 95: 59-62.
8 Mansilha A, Araujo F, Severo M. et al. The association between the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor-1 gene and deep venous thrombosis in young people. Phlebology 2005; 20: 48-52.
9 Segui R, Estelles A, Mira Y. et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects. Br J Haematol 2000; 111: 122-128.
10 Akar N, Yilmaz E, Akar E. et al. Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients withn and without FV1691 G-A. Thromb Res 2000; 97: 227-230.
11 Sartori MT, Danesin C, Saggiorato G. et al. The PAI-1 gene 4G/5G polymorphism and deep vein thrombosis in patients with inherited thrombophilia. Clin Apl Thromb Hemost 2003; 9: 299-307.
12 Tassies D, Espinosa G, Munoz-Rodriguez FJ. et al. The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome. Arthritis Rheum 2000; 43: 2349-2358.
13 Morange PE, Henry M, Tregouet D. et al. The A –844G polymorhism in the PAI-1 gene is associated with a higher risk of venous thrombosis in factor V Leiden carriers. Arterioscler Thromb Vasc Biol 2000; 20: 1387-1391.
14 Gurgey A, Balta G, Boyvat A. Factor V Leiden mutation and PAI-1 gene 4G/5G genotype in thrombotic patients with Behcet’s disease. Blood Coag Fibrinolysis 2003; 14: 121-124.
15 Yasuda S, Tsutsumi A, Atsumi T. et al. Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with antiphospholipid antibodies. J Rheumatol 2002; 2: 1192-1197.
16 Stegnar M, Uhrin P, Peternel P. et al. The 4G/5G polymorphism in the promoter of plasminogen acti activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism. Thromb Haemost 1998; 79: 975-979.
17 Sartori MT, Wiman B, Vettore S. et al. 4G/5G polymorphism of PAI-1 gene promoter and fibrinolytic capacity in patients with deep vein thrombosis. Thromb Haemost 1998; 80: 956-960.
18 Meglic L, Stegnar M, Milanez T. et al. Factor V Leiden, prothrombin 20210 G/A, methylenetetrahydrofolate reductase 677C/T, and plasminogen activator inhibitor 4G/5G polymorphism in women with pregnancy- related venous thromboembolism. Eur J Obstet Gynecol Reprod Biol 2003; 111: 157-163.
19 Juhan-Vague I, Vague P, Alessi MC. et al. Relationships between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabetes Metab 1987; 13: 331-336.
20 Petiti DB. Meta-analysis, decision analysis and cost-effectiveness analysis, vol 24:. Oxford University Press; 1994
21 Berman NG, Parker RA. Meta-analysis: Neither quick nor easy. BMC Medical Res Meth 2002; 2: 10.
22 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557-560.
23 DerSimonian R, Laird N. Meta-analysis in clinical trials. Contr Clin Trials 1986; 7: 177-188.
24 Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrica 1965; 61: 644-646.
25 Egger M, Davey Smith G, Schneider M. et al. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629-634.
26 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088-1101.
27 Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med 1999; 18: 2693-2708.
28 Lau J, Antman EM, Jimenez-Silva J. et al. Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992; 327: 248-254.
29 Zoller B, Garcia de Frutos P, Dahlback B. A common 4G allele in the promoter of the plasminogen activator inhibitor –1 (PAI-1) gene as a risk factor for pulmonary embolism and arterial thrombosis in hereditary protein S deficiency. Thromb Haemost 1998; 79: 802-807.
30 Junker R, Nabavi DG, Wolff E. et al. Plasminogen activator inhibitor-1 4G/4G-genotype is associated with cerebral sinus thrombosis in factor V Leiden carriers. Thromb Haemost 1998; 80: 706-707.
31 Espinosa G, Font J, Tassies D. et al. Vascular involvement in Behcet’s disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med 2002; 112: 37-43.
32 Barcellona D, Fenu L, Cauli C. et al. Allele 4G of gene PAI-1 associated with prothrombin mutation G20210A increases the risk for venous thrombosis. Thromb Haemost 2003; 90: 1061-1064.
33 Balta G, Altay C, Gurgey A. PAI-1 gene 4G/5G genotype: a risk factor for thrombosis in vessels of internal organs. Am J Hematol 2002; 71: 89-93.
34 Hooper WC, Lally C, Austin H. et al. The role of the t-PA I/D and PAI-1 4G/5G polymorphisms in African- American adults with a diagnosis of myocardial infarction or venous thromboembolism. Thromb Res 2000; 99: 223-230.
35 Mattes D, Weger M, Renner W. et al. Role of angiotensin- converting enzyme insertion/deletion and plasminogen activator inhibitor-1 4G/5G gene polymorphisms in retinal vein occlusion. J Thromb Haemost 2005; 3: 2583-2584.
36 Glueck CJ, Bell H, Vadlamani L. et al. Heritable thrombophilia and hypofibrinolysis; possible causes of retinal vein occlusion. Arch Ophthalmol 1999; 117: 41-43.
37 Gori AM, Marcucci R, Fatini C. et al. Impaired fibrinolysis in retinal vein occlusion: a role for genetic determinants of PAI-1 levels. Thromb Haemost 2004; 92: 54-60.
38 Folsom AR, Cushman M, Heckbert SR. et al. Prospective study of fibrinolytic markers and venous thromboembolism. J Clin Epidem. 2003: 598-603.
39 Visanji JM, Seargent J, Tahri D. et al. Influence of the –6756 4G/5G dimorphism of the plasminogen activator inhibitor 1 promoter on thrombotic risk in patients with factor V Leiden. Br J Haematol 2000; 100: 135-138.
40 Henry M, Chomiki N, Scarabin PY. et al. Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 1997; 17: 851-858.