Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study

Experimental and clinical research supports a direct link between activation of the renin–angiotensin system and production of plasminogen activator inhibitor-1 (PAI-1), the primary physiologic inhibitor of tissue plasminogen activator. Several studies have reported higher PAI-1 levels in individuals carrying the deletion (D) allele of the angiotensin-converting enzyme (ACE) gene. We investigated the association between ACE genotypes and plasma PAI-1 levels in a family study of 577 women and 428 men from four US communities. Participants were between 25 and 84 years of age without evidence of coronary heart disease (CHD). Mean geometric plasma PAI-1 levels adjusted for ethnicity were 17.4, 17.9, and 18.1 ng/ml in participants with the DD, insertion–deletion (ID), and II genotypes, respectively (P = 0.89 for difference). We found no associations between ACE I/D genotypes and plasma PAI-1 antigen concentrations in a subset of participants without major CHD risk factors (hypertension, hypercholesterolemia, overweight, smoking, diabetes) or in a small sample of African–Americans. Our findings suggest that the ACE insertion/deletion polymorphism has relatively little, if any, influence on circulating PAI-1 levels in the population at large.

[1]  D. Newby,et al.  Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. , 1999, Circulation.

[2]  S. Vettore,et al.  Determinants of plasma levels of plasminogen activator inhibitor-1 : A study of normotensive twins. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[3]  H. Vetter,et al.  Effects of captopril on fibrinolytic function in healthy humans. , 1997, European journal of medical research.

[4]  D. Vaughan,et al.  Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. , 1998, Hypertension.

[5]  J. Pankow,et al.  Segregation analysis of plasminogen activator inhibitor-1 and fibrinogen levels in the NHLBI family heart study. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[6]  J. Pankow,et al.  Angiotensinogen and angiotensin converting enzyme genotypes and carotid atherosclerosis: the atherosclerosis risk in communities and the NHLBI family heart studies. , 1998, Atherosclerosis.

[7]  W. Knowler,et al.  Angiotensin-1-converting enzyme (ACE) gene polymorphism, plasma ACE levels, and their association with the metabolic syndrome and electrocardiographic coronary artery disease in Pima Indians. , 1998, Metabolism: clinical and experimental.

[8]  M. Margaglione,et al.  PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[9]  H. Harn,et al.  Plasminogen activator inhibitor-1 and angiotensin I converting enzyme gene polymorphism in patients with hypertension. , 1998, American journal of hypertension.

[10]  G. Siest,et al.  Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentrations: a family study with part of the Stanislas Cohort. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[11]  W. R. Lee,et al.  Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[12]  U. de Faire,et al.  Moderate genetic influences on plasma levels of plasminogen activator inhibitor-1 and evidence of genetic and environmental influences shared by plasminogen activator inhibitor-1, triglycerides, and body mass index. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[13]  M. Margaglione,et al.  Plasminogen activator inhibitor-1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward: relation to polymorphisms of PAI-1 and angiontensin converting enzyme (ACE) genes. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[14]  M. Pfeffer,et al.  Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. HEART Study Investigators. , 1997, Circulation.

[15]  K. Nakagawa,et al.  Angiotensin II Increases Plasminogen Activator Inhibitor-1 and Tissue Factor mRNA Expression without Changing that of Tissue Type Plasminogen Activator or Tissue Factor Pathway Inhibitor in Cultured Rat Aortic Endothelial Cells , 1997, Thrombosis and Haemostasis.

[16]  D. Arveiler,et al.  Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[17]  X. Jeunemaître,et al.  Does long‐term angiotensin converting enzyme inhibition affect the concentration of tissue‐type plasminogen activator‐plasminogen activator inhibitor‐1 in the blood of patients with a previous myocardial infarction , 1997, Coronary artery disease.

[18]  I. Borecki,et al.  Associations between candidate loci angiotensin-converting enzyme and angiotensinogen with coronary heart disease and myocardial infarction: the NHLBI Family Heart Study. , 1997, Annals of epidemiology.

[19]  D. Vaughan,et al.  The Renin-Angiotensin and fibrinolytic systems co-conspirators in the pathogenesis of ischemic cardiovascular disease. , 1996, Trends in cardiovascular medicine.

[20]  N. Samani,et al.  A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. , 1996, Circulation.

[21]  D C Rao,et al.  NHLBI Family Heart Study: objectives and design. , 1996, American journal of epidemiology.

[22]  P. Talmud,et al.  The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance? , 1995, Circulation.

[23]  D. Vaughan,et al.  Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. , 1995, The Journal of clinical investigation.

[24]  B. Sobel,et al.  Attenuation of the synthesis of plasminogen activator inhibitor type 1 by niacin. A potential link between lipid lowering and fibrinolysis. , 1995, Circulation.

[25]  J. Connell,et al.  Enhanced pressor response to angiotensin I in normotensive men with the deletion genotype (DD) for angiotensin-converting enzyme. , 1995, Hypertension.

[26]  D. Vaughan,et al.  Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. , 1995, The Journal of clinical investigation.

[27]  L. Aiello,et al.  Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. , 1995, The Journal of clinical investigation.

[28]  K. Alberti,et al.  Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. , 1994, Journal of the American College of Cardiology.

[29]  A. Maseri,et al.  Angiotensin II Increases Plasminogen Activator Inhibitor Type 1 and Tissue‐Type Plasminogen Activator Messenger RNA in Cultured Rat Aortic Smooth Muscle Cells , 1994, Circulation.

[30]  K. Sell,et al.  Mistyping ACE heterozygotes. , 1993, PCR methods and applications.

[31]  P. Ridker,et al.  Stimulation of Plasminogen Activator Inhibitor In Vivo by Infusion of Angiotensin II Evidence of a Potential Interaction Between the Renin‐Angiotensin System and Fibrinolytic Function , 1993, Circulation.

[32]  B. Pitt,et al.  Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions , 1992, The Lancet.

[33]  Philippe Amouyel,et al.  Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction , 1992, Nature.

[34]  E. J. Brown,et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. , 1992, The New England journal of medicine.

[35]  L. Tiret,et al.  Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. , 1992, American journal of human genetics.

[36]  F. Soubrier,et al.  PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). , 1992, Nucleic acids research.

[37]  P Corvol,et al.  An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. , 1990, The Journal of clinical investigation.

[38]  M. Alessi,et al.  Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. , 1988, Blood.

[39]  S. Zeger,et al.  Longitudinal data analysis using generalized linear models , 1986 .