Plasminogen Activator Inhibitor-1 (PAI-1) Gene 4G/5G Promoter Polymorphism is Seen in Higher Frequency in the Indian Patients With Deep Vein Thrombosis

Abstract

Introduction: A number of prothrombotic and fibrinolytic disorders may lead to venous thrombosis. A 4G/5G polymorphism located in the promoter region of plasminogen activator inhibitor-1 (PAI-1) gene has been found to be commonly associated with the levels of PAI-1 and might be a risk factor for deep vein thrombosis (DVT). The aim of this study was to look for the potential association of this polymorphism with DVT in the Asian Indian population. Material and methods: A total of 110 consecutive patients (M:F = 62:48) with idiopathic DVT and equal number of age- and sex-matched healthy controls were the study participants. All study participants were typed for the PAI-1 4G/ 5G polymorphism, factor V Leiden, factor V Hong Kong/Cambridge mutations, and HR2 haplotype. Result: The variant allele for the PAI-1 4G/5G polymorphism showed both genotypic (P = .0013, χ² = 10.303; odds ratio [OR] = 3.75) as well as allelic association (P = .0004, χ² = 12.273; OR = 1.99) with DVT. Factor V Leiden and factor V HR2 haplotype were observed in 10 (9.0%) and 13 (11.8%) patients, respectively. None of the study participants showed the factor V Hong Kong Cambridge mutations. Conclusion: Our study shows the association of 4G allele with DVT in Asian Indian population. The higher prevalence of 4G polymorphism in patients with DVT (compared with controls) seen in our study is in concordance with previous reports from the Caucasian population.

Keywords

PAI-1 deep vein thrombosis (DVT)4G/5G polymorphism factor V Leiden (FVL)

References

Biswas A. , Bajaj J. , Ranjan R. , et al. Factor V Leiden: is it the chief contributor to activated protein C resistance in Asian Indian patients with deep vein thrombosis? Clin Chim Acta. 2008;392:21-24.

Alessi M. , Juhan-Vague I. , Kooistra T. , Declerck PJ , Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor-1 by the human hepatocellular cell line HepG2. Thromb Haemost. 1988;60:491-494.

Sartori MT , Wiman B. , Vettore S. , Dazzi F. , Girolami A. , Patrassi GM 4G/5G polymorphism of PAI-1 gene promoter & fibrinolysis capacity in patients with deep vein thrombosis. Thromb Hemost. 1998;80:956-960.

Juhan-Vague I. , Vaghe P. , Alessi M. , et al. Relationship between plasma insuli, triglycerides, body mass index and plasminogen activator inhibitor-1. Diabetes Metab. 1987;13:331-336.

Blasiak J. , Smolarz B. Plasminogen activator inhibitor-1I (PAI-1) gene 4G/5G promoter polymorphism is not associated with breast cancer. Acta Biochimica Polonica . 2000;47:191-199.

Falk G. , Almqvist A. , Nordehen A. , Svensson H. , Wiman B. Allele specific PCR for a detection of a sequence polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene. Fibrinolysis. 1995;9:170-174.

Rocha E. , Paramo JA The relationship between impaired fibrinolysis and coronary heart disease: a role for PAI-1. Fibrinolysis. 1994;8:294-303.

Juhan Vague I. , Valadier J. , Alessi MC , et al. Deficient t-PA release and elevated PA inhibitor in patients with spontaneous or recurrent deep venous thrombosis . Thromb Haemost. 1987;57:67-72.

Jansson JH , Nilsson TK , Olofsson BO Tissue plasminogen activator inhibitor and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris. Eur Heart J. 1991;2:157-161.

10.

Johansson L. , Jansson HJ , Boman K. , Nilsson KT , Stegmayr B. , Hallmans G. Tissue plasminogen activator, plasminogen activator inhibitor-1 and tissue plasminogen activator/ plasminogen activator inhibitor-1 complex as a risk factors for the development of a first stroke . Stroke. 2000;1:26-32.

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 Appl Thromb Hemost . 2003;9:299-307.

12.

Eriksson P. , Kallin B. , Van’t Hoft FM , Bavenholm P. , Hamsten A. Allele specific increase in basal transcription of the plasminogen activator inhibitor-1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995;92:1851-1855.

13.

Mansfield MW , Stickland MH , Grant PJ Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasians patients, with non insulin dependent diabetes mellitus. Thromb Haemost. 1995;74:842-847.

14.

Wiklund GP , Nilsson L. , Ardnor NS , et al. Plasminogen activator inhibitor-1 4G/5G polymorphism and risk of stroke. Replicated findings in two nested case-control studies based on independent cohorts. Stroke. 2005;36: 1661-1665.

15.

Grubic N. , Stegnar M. , Peternel P. , Keider A. , Binder BR A novel G/A and the 4G/5G polymorphism with in the promoter of the plasminogen activator inhibitor-1 gene in patients with deep vein thrombosis. Thromb Res. 1996;84:431-443.

16.

Ridker PM , Hennekens CH , Lindpaintner K. , Stampfer MJ , Miletich JP Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor in a large cohort of US men. Circulation. 1997;95:59-62.

17.

Vague P. , Juhan-Vague I. , Aillaud MF , et al. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level, and relative body weight in normal and obese objects. Metabolism. 1986 ;35:250-253.

18.

Segui R. , Estelles A. , Mira Y. , et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subject with genetic thrombolic defects. Br J Haematol. 2000;111:122-128.

19.

Naran NH , Chetty N. , Crowther NJ The influence of metabolic syndrome components on plasma PAI-1 concentrations is modified by the PAI-1 4G/5G genotype and ethnicity. Atherosclerosis . 2008;196:155-163.

20.

Pegoraro RJ , Ranjith N. Plasminogen activator inhibitor type-1 (PAI-1) and platelet glycoprotein IIIa (PG IIIa) polymorphism in young Asian Indians with acute myocardial infarction. Cardiovasc J S Afr. 2005;16: 266-270.

21.

Kostka H. , Kuhlisch E. , Schellong S. , Siegert G. Polymorphisms in the TAFI gene and the risk of venous thrombosis. Clin Lab. 2003;49:645-647.

22.

Martini CH , Brandts A. , de Bruijne EL , et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol. 2006;134:92-94.