Download PDF
Thromb Haemost 2000; 84(01): 78-82
DOI: 10.1055/s-0037-1613971
Commentary
Schattauer GmbH

Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Polymorphism, Coronary Thrombosis, and Myocardial Infarction in Middle-aged Finnish Men who Died Suddenly

Jussi Mikkelsson
1   From the Medical School, University of Tampere and Tampere University Hospital, Tampere, Finland
,
Markus Perola
2   Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland
,
Ulla Wartiovaara
3   Department of Clinical Chemistry and Biomedicine, Helsinki University Central Hospital, Helsinki, Finland
,
Leena Peltonen
2   Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland
,
Aarno Palotie
3   Department of Clinical Chemistry and Biomedicine, Helsinki University Central Hospital, Helsinki, Finland
,
Antti Penttilä
4   Department of Forensic Medicine, University of Helsinki, Finland
,
Pekka J. Karhunen
1   From the Medical School, University of Tampere and Tampere University Hospital, Tampere, Finland
5   Department of Clinical Pathology and Forensic Medicine, University of Kuopio, Finland
› Author Affiliations
Further Information

Publication History

Received 22 December 1999

Accepted after resubmission 23 February 2000

Publication Date:
10 December 2017 (online)

    Permissions and Reprints

Summary

High plasminogen activator inhibitor-1 (PAI-1) plasma levels increase future risk of myocardial infarction (MI). The 4G allele of the 4G/5G polymorphism of the PAI-1 gene has been associated with increased plasma levels of PAI-1. The association of the PAI-1 polymorphism with coronary narrowings, coronary thrombosis and myocardial infarction (MI) was studied in a prospective autopsy series of 300 middle-aged Caucasian Finnish men (33 to 69 yrs) suffering sudden out-of-hospital death (Helsinki Sudden Death Study). The 4G allele was found in 76.8% of men with sudden cardiac death (SCD) compared to 67.5% in men who died accidentally and 63.2% in men who died of other diseases (p = 0.08 and p = 0.055, respectively). Men possessing the 4G allele had more often acute MI (OR 3.5; p <0.05) and coronary thrombosis (OR 5.5; p = 0.01) compared to 5G homozygotes. 5G homozygotes, comprising one third of the men in our study, seem to be at a decreased risk of thrombosis, whereas carriers of the common 4G allele have an increased risk of thrombosis, AMI and possibly SCD compared to 5G homozygotes.

Keywords

PAI-1 - MI - sudden cardiac death - polymorphism - coronary thrombosis
 

  • References

  • 1 Marenberg ME, Risch N, Berkman LF, Floderus B, De Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. New Engl J Med 1994; 330: 1041-6.
    CrossrefPubMedGoogle Scholar
  • 2 Hippe M, Vestbo J, Hein HO, Borch-Johnsen K, Jensen G, Sorensen TIA. Familial predisposition and susceptibility to the effect of other risk factors for myocardial infarction. J Epid Comm Health 1999; 53: 269-76.
    CrossrefPubMedGoogle Scholar
  • 3 Sexton PT, Walsh J, Jamrozik K, Parsons R. Risk factors for sudden unexpected cardiac death in Tasmanian men. Aust N Z J Med 1997; 27: 45-50.
    CrossrefPubMedGoogle Scholar
  • 4 Mikkelsson J, Perola M, Laippala P, Penttilä A, Karhunen PJ. Glycoprotein IIIa PlA1/A2 polymorphism and sudden cardiac death. J Am Coll Cardiol. In press.
    PubMedGoogle Scholar
  • 5 Ilveskoski E, Perola M, Lehtimaki T, Laippala P, Savolainen V, Pajarinen J, Penttila A, Lalu KH, Mannikko A, Liesto KK, Koivula T, Karhunen PJ. Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men. An autopsy study. Circulation 1999; 100: 608-13.
    CrossrefPubMedGoogle Scholar
  • 6 Badimon JJ, Fuster V, Chesebro JH, Badimon L. Coronary Atherosclerosis: A Multifactorial Disease. Circulation 1993; 87: II3-II16.
    PubMedGoogle Scholar
  • 7 Fuster V, Badimon JJ, Badimon L, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
    CrossrefPubMedGoogle Scholar
  • 8 Farb A, Burke AP, Kolodgie FD, Virmani R. Risk profiles are more abnormal and acute thrombi more frequent in young men with sudden coronary death. JACC 1999; 33 (Suppl 2A): 324A.
    CrossrefPubMedGoogle Scholar
  • 9 Burke AP, Farb A, Malcom GT, Liang Y, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. New Engl J Med 1997; 336: 1276-82.
    CrossrefPubMedGoogle Scholar
  • 10 Zhu Y, Carmeliet P, Fay WP. Plasminogen activator inhibitor-1 is a major determinant of arterial thrombosis resistance. Circulation 1999; 99: 3050-5.
    CrossrefPubMedGoogle Scholar
  • 11 Pawse AR, Tarachand U. Clot lysis: role of plasminogen activator inhibitors in haemostasis and therapy. Indian journal of experimental biology 1997; 35: 545-52.
    PubMedGoogle Scholar
  • 12 Wiman B. Plasminogen activator inhibitor 1 in thrombotic disease. Current opinion in hematology 1996; 03: 372-8.
    CrossrefPubMedGoogle Scholar
  • 13 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 02: 3-9.
    PubMedGoogle Scholar
  • 14 Scarabin PY, Aillaud MF, Amouyel P, Evans A, Luc G, Ferrieres J, Arveiler D, Juhan-Vague I. Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction – the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction. Thromb Haemost 1998; 80: 749-56.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Mansfield MW, Stickland MH, Grant PJ. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in noninsulin-dependent diabetes. Thromb Haemost 1995; 74: 1032-4.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Farb A, Burke AP, Kolodgie FD, Mannan P, Liang Y, Smialek J, Virmani R. Plasminogen activator inhibitor-1 is a determinant of coronary thrombosis in sudden cardiac death. JACC 1996; 27 (2 Suppl A): 108.
    PubMedGoogle Scholar
  • 17 Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plasminogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arteriosclerosis, Thrombosis and Vascular Biology 1997; 17: 33-7.
    CrossrefPubMedGoogle Scholar
  • 18 Margaglione M, Grandone E, Vecchione G, Cappucci G, Giuliani N, Colaizzo D, Celentano E, Panico S, Di Minno G. Plasminogen activator inhibitor (PAI-1) antigen plasma levels in subjects attending a metabolic ward: relation to polymorphisms of PAI-1 and angiotensin converting enzyme (ACE) genes. Arteriosclerosis, Thrombosis and Vascular Biology 1997; 17: 2082-7.
    CrossrefPubMedGoogle Scholar
  • 19 Margaglione M, Cappucci G, d’Addedda M, Colaizzo D, Giuliani N, Vecchione G, Mascolo G, Grandone E, Di Minno G. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation of environmental and genetic determinants. Arteriosclerosis, Thrombosis and Vascular Biology 1998; 18: 562-7.
    CrossrefPubMedGoogle Scholar
  • 20 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP. 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. Thromb Haemost 1995; 74: 837-41.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allelespecific increase in basal transcription of the plasminogen activator inhibitor-1 gene is associated with myocardial infarction. PNAS 1995; 92: 1851-5.
    CrossrefPubMedGoogle Scholar
  • 22 Pastinen T, Perola M, Niini P, Terwilliger J, Salomaa V, Vartiainen E, Peltonen L, Syvänen A. Array-based multiplex analysis of candidate genes reveals two independent and additive risk factors for myocardial infarction in the Finnish population. Human molecular genetics 1998; 07: 1453-62.
    CrossrefPubMedGoogle Scholar
  • 23 Iacoviello L, Burzotta F, Di Castelnuovo A, Zito F, Marchioli R, Donati MB. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: A meta-analysis. Thromb Haemost 1998; 80: 1029-30.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Iwai N, Shimoike H, Nakamura Y, Tamaki S, Kinoshita M. The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated with the time course of progression to acute coronary syndromes. Atherosclerosis 1998; 136: 109-14.
    CrossrefPubMedGoogle Scholar
  • 25 Heijmans BT, Westendorp RGJ, Knook DL, Kluft C, Slagboom PE. Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort. JACC 1999; 34: 1176-83.
    CrossrefPubMedGoogle Scholar
  • 26 Junker R, Heinrich J, Schulte H, Tataru M, Köhler E, Schönfeld R, Nowak-Göttl U, Assmann G. Plasminogen activator inhibitor-1 4G/5G polymorphism and factor V Q506 mutation are not associated with myocardial infarction in young men. Blood coagulation and fibrinolysis 1998; 09: 597-602.
    CrossrefPubMedGoogle Scholar
  • 27 Doggen CJ, Bertina RM, Cats VM, Reitsma PH, Rosendaal FR. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction. Thromb Haemost 1999; 82: 115-20.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 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 gene in a large cohort of US men. Circulation 1997; 95: 59-62.
    CrossrefPubMedGoogle Scholar
  • 29 Ardissino D, Mannucci PM, Merlini PA, Duca F, Fetiveau R, Tagliabue L, Tubaro M, Galvani M, Ottani F, Ferrario M, Corral J, Margaglione M. Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood 1999; 94: 46-51.
    PubMedGoogle Scholar
  • 30 Anderson JL, Muhlestein JB, Habashi J, Carlquist JF, Bair TL, Elmer SP, Davis BP. Lack of association of a common polymorphism of the plasminogen activator inhibitor-1 gene with coronary artery disease and myocardial infarction. JACC 1999; 34: 1778-83.
    CrossrefPubMedGoogle Scholar
  • 31 Weman SM, Salminen U-S, Penttilä A, Männikkö A, Karhunen PJ. Post-mortem cast angiography in the diagnostics of graft complications in patients with fatal outcome following coronary artery bypass grafting (CABG). Int J Legal Med 1999; 112: 107-14.
    CrossrefPubMedGoogle Scholar
  • 32 Syvänen AC, Aalto-Setälä K, Harju L, Kontula K, Söderlund H. A primerguided nucleotide incorporation assay in the genotyping of apolipoprotein E. Genomics 1990; 08: 684-692.
    CrossrefPubMedGoogle Scholar
  • 33 Kim DK, Kim JW, Kim S, Gwon HC, Ryu JC, Huh JE, Choo JA, Choi Y, Rhee CH, Lee WR. Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. ATVB 1997; 17: 3242-7.
    PubMedGoogle Scholar
  • 34 Barrett-Connor E, Khaw K. Family history of heart attack as an independent predictor of death due to cardiovascular disease. Circulation 1984; 69: 1065-9.
    CrossrefPubMedGoogle Scholar
  • 35 Friedlander Y, Siscovick DS, Weinmann S, Austin MA, Psaty BM, Lemaitre RN, Arbogast P, Raghunathan TE, Cobb LA. Family history as a risk factor for primary cardiac arrest. Circulation 1998; 97: 155-60.
    CrossrefPubMedGoogle Scholar
  • 36 Jouven X, Desnos M, Guerot C, Ducimetiere P. Predicting sudden death in the population. The Paris prospective study I. Circulation 1999; 99: 1978-83.
    CrossrefPubMedGoogle Scholar
  • 37 Gardemann A, Lohre J, Katz N, Tillmanns H, Hehrlein FW, Haberbosch W. The 4G/4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost 1999; 82: 1121-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Wartiovaara U, Perola M, Mikkola H, Tötterman K, Savolainen V, Penttilä A, Grant PJ, Tikkanen MJ, Vartiainen E, Karhunen PJ, Peltonen L, Palotie A. Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males. Atherosclerosis 1999; 142: 295-300.
    CrossrefPubMedGoogle Scholar