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Thromb Haemost 2005; 93(01): 92-96
DOI: 10.1160/TH04-09-0560
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The plasminogen activator inhibitor (PAI-1) 4G/5G promoter polymorphism and PAI-1 levels in ischemic stroke

A case-control study
Mary-Lou van Goor
1   Departments of Neurology, The Netherlands
,
Encarna Gómez García
2   Hematology of the Erasmus Medical Center Rotterdam, The Netherlands
,
Frank Leebeek
2   Hematology of the Erasmus Medical Center Rotterdam, The Netherlands
,
Geert-Jan Brouwers
2   Hematology of the Erasmus Medical Center Rotterdam, The Netherlands
,
Peter Koudstaal
1   Departments of Neurology, The Netherlands
,
Diederik Dippel
1   Departments of Neurology, The Netherlands
› Author Affiliations
Financial support: This study was supported by a grant from the Revolving Fund of the Erasmus MC, and by the Stichting Neurovasculair Onderzoek Rotterdam.
Further Information

Correspondence to:

Mary-Lou PJ van Goor
Erasmus Medical Center Rotterdam
Department of Neurology
PO Box 2040, 3000 CA Rotterdam
The Netherlands
Phone: +31 10 4639222   
Fax: +31 10 4089446   

Publication History

Received 02 September 2004

Accepted after revision 11 October 2004

Publication Date:
14 December 2017 (online)

Also available at
 
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Summary

High levels of plasminogen activator inhibitor type 1 (PAI-1) have been implicated as a risk factor for cardiovascular disease, but its precise role remains controversial.The 4G allele of the PAI-1 4G/5G promoter polymorphism is associated with higher levels of PAI-1. We studied the relationship between ischemic stroke and the PAI-1 4G/5G polymorphism and PAI-1 antigen levels. We performed a case-control study among patients aged 18–75 years with first ischemic stroke, confirmed by CT.All patients were screened for cardiovascular risk factors, cardiac disorders and large vessel disease. We excluded patients with a definite non-atherosclerotic cause of the stroke and patients using oral anticoagulants. Population-controls were age -and sex-matched, without a history of stroke, and of the Caucasian race.Venous blood samples were taken for PAI-1 4G/5G polymorphism and PAI-1 level one week after stroke.We included 124 patients and 125 controls. Mean age was 56 yrs (range 18 to 75 yrs). Sixty one patients (50%) and 58 (47%) controls were heterozygous for the PAI-1 4G/5G polymorphism.The homozygous 4G/4G genotype was found in 33 patients (27%) and in 36 controls (29%). The odds ratio of ischemic stroke associated with 4G-carriers versus 5G/5G homozygotes was 1.0 (95% CI: 0.6–1.8).The relative risk of ischemic stroke associated with the level of PAI-1 in the upper quartile was 0.73 (95%CI: 0.4 to 1.4). Neither the PAI-1 4G/5G polymorphism nor the PAI-1 antigen level is a strong risk factor for ischemic stroke.


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Keywords

PAI-1 4G/5G polymorphism - ischemic stroke - case-control - PAI-1 level

 


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  • References

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  • 13 Bang CO, Park HK, Ahn MY. et al 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene and insertion/deletion polymorphism of the tissue- type plasminogen activator gene in atherothrombotic stroke. Cerebrovasc Dis 2001; 11: 294-9.
    CrossrefPubMedSearch in Google Scholar
  • 14 Crainich P, Jenny NS, Tang Z. et al Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. J Thromb Haemost 2003; 1: 1799-804.
    CrossrefPubMedSearch in Google Scholar
  • 15 Festa A, D'Agostino RA, Rich SS. et al Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, hispanics, and non-hispanic whites. Circulation 2003; 107: 2422-7.
    CrossrefPubMedSearch in Google Scholar
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    CrossrefPubMedSearch in Google Scholar
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    CrossrefPubMedSearch in Google Scholar
  • 18 Mahoney I F, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965; 14: 61-5.
    PubMedSearch in Google Scholar
  • 19 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977; 74: 5463-7.
    CrossrefPubMedSearch in Google Scholar
  • 20 Falk G, Almqvist A, Nordenhem A. Allele specific PCR for detection of a sequence polymorphism in the promotor region of the plasminogen activator inhibitor- 1 (PAI-1) gene. Fibrinolysis 1995; 9: 170-4.
    PubMedSearch in Google Scholar
  • 21 Declerck PJ. Plasminogen activator inhibitor-1 (PAI-1) antigen. Laboratory techniques in thrombosis. A manual 2000; 239-45. (?¦ Title of manual).
    PubMedSearch in Google Scholar
  • 22 Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Ridker PM, Hennekens CH, Lindpaintner 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.
    CrossrefPubMedSearch in Google Scholar
  • 24 Juhan-Vague I, Alessi M-C, Mavri A. et al Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 2003; 1: 1575-9.
    CrossrefPubMedSearch in Google Scholar
  • 25 Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2004; 342: 1792-801.
    PubMedSearch in Google Scholar

Correspondence to:

Mary-Lou PJ van Goor
Erasmus Medical Center Rotterdam
Department of Neurology
PO Box 2040, 3000 CA Rotterdam
The Netherlands
Phone: +31 10 4639222   
Fax: +31 10 4089446   

  • References

  • 1 Ye S, Green FR, Scarabin PY. et al The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude Cas Temoins de I'nfarctus du Myocarde. Thromb Haemost 1995; 74: 837-41.
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Catto AJ, Carter AM, Stickland M. et al Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism and levels in subjects with cerebrovascular disease. Thromb Haemost 1997; 77: 730-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Hamsten A, de Faire U, Walldius G. et al Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
    PubMedSearch in Google Scholar
  • 4 Ny T, Sawdey M, Lawrence D. et al Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc Natl Acad Sci U S A 1986; 83: 6776-80.
    CrossrefPubMedSearch in Google Scholar
  • 5 Wiman B, Chmielewska J, Ranby M. Inactivation of tissue plasminogen activator in plasma. Demonstration of a complex with a new rapid inhibitor. J Biol Chem 1984; 259: 3644-7.
    PubMedSearch in Google Scholar
  • 6 Strandberg L, Lawrence D, Ny T. The organization of the human-plasminogen-activator-inhibitor-1 gene. Implications on the evolution of the serine-protease inhibitor family. Eur J Biochem 1988; 176: 609-16.
    CrossrefPubMedSearch in Google Scholar
  • 7 Dawson S, Hamsten A, Wiman B. et al Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991; 11: 183-90.
    CrossrefPubMedSearch in Google Scholar
  • 8 Boekholdt SM, Bijsterveld NR, Moons AH. et al Genetic variation in coagulation and fibrinolytic pro- teins and their relation with acute myocardial infarction: a systematic review. Circulation 2001; 104: 3063-8.
    CrossrefPubMedSearch in Google Scholar
  • 9 Endler G, Lalouschek W, Exner M. et al The 4G/4G genotype at nucleotide position –675 in the promotor region of the plasminogen activator inhibitor 1 (PAI-1) gene is less frequent in young patients with minor stroke than in controls. Br J Haematol 2000; 110: 469-71.
    CrossrefPubMedSearch in Google Scholar
  • 10 Hindorff LA, Schwartz SM, Siscovick DS. et al The association of PAI-1 promoter 4G/5G insertion/ deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovasc Risk 2002; 9: 131-7.
    PubMedSearch in Google Scholar
  • 11 Hoekstra T, Geleijnse JM, Kluft C. et al 4G/4G genotype of PAI-1 gene is associated with reduced risk of stroke in elderly. Stroke 2003; 34: 2822-8.
    CrossrefPubMedSearch in Google Scholar
  • 12 Roest M, van der Schouw YT, Banga JD. et al Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000; 101: 67-70.
    CrossrefPubMedSearch in Google Scholar
  • 13 Bang CO, Park HK, Ahn MY. et al 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene and insertion/deletion polymorphism of the tissue- type plasminogen activator gene in atherothrombotic stroke. Cerebrovasc Dis 2001; 11: 294-9.
    CrossrefPubMedSearch in Google Scholar
  • 14 Crainich P, Jenny NS, Tang Z. et al Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. J Thromb Haemost 2003; 1: 1799-804.
    CrossrefPubMedSearch in Google Scholar
  • 15 Festa A, D'Agostino RA, Rich SS. et al Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, hispanics, and non-hispanic whites. Circulation 2003; 107: 2422-7.
    CrossrefPubMedSearch in Google Scholar
  • 16 Bamford J, Sandercock P, Dennis M. et al Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337: 1521-6.
    CrossrefPubMedSearch in Google Scholar
  • 17 Adams Jr. HP, Bendixen BH, Kappelle LJ. et al Classification of subtype of acute ischemic stroke. Stroke 1993; 24: 35-41.
    CrossrefPubMedSearch in Google Scholar
  • 18 Mahoney I F, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965; 14: 61-5.
    PubMedSearch in Google Scholar
  • 19 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977; 74: 5463-7.
    CrossrefPubMedSearch in Google Scholar
  • 20 Falk G, Almqvist A, Nordenhem A. Allele specific PCR for detection of a sequence polymorphism in the promotor region of the plasminogen activator inhibitor- 1 (PAI-1) gene. Fibrinolysis 1995; 9: 170-4.
    PubMedSearch in Google Scholar
  • 21 Declerck PJ. Plasminogen activator inhibitor-1 (PAI-1) antigen. Laboratory techniques in thrombosis. A manual 2000; 239-45. (?¦ Title of manual).
    PubMedSearch in Google Scholar
  • 22 Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-4.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Ridker PM, Hennekens CH, Lindpaintner 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.
    CrossrefPubMedSearch in Google Scholar
  • 24 Juhan-Vague I, Alessi M-C, Mavri A. et al Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 2003; 1: 1575-9.
    CrossrefPubMedSearch in Google Scholar
  • 25 Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2004; 342: 1792-801.
    PubMedSearch in Google Scholar

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