© 1997 American Heart Association, Inc.
Articles |
Polymorphism of Angiotensin Converting Enzyme Gene Is Associated With Circulating Levels of Plasminogen Activator Inhibitor-1
Correspondence to Won-Ro Lee, MD, PhD, Division of Cardiology, Department of Medicine, Samsung Medical Center, Sung Kyun Kwan University, College of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135–230, Korea. E-mail dkkim{at}smc.samsung.co.kr
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Abstract |
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Abstract The deletion (D) allele of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is strongly associated with an increased level of circulating ACE. The ACE gene polymorphism may influence the production of angiotensin II (Ang II). It has been shown that Ang II modulates fibrinolysis, that is, Ang II increases plasminogen activator inhibitor-1 (PAI-1) mRNA and plasma PAI-1 levels in vitro and in vivo. Considered together, we tested the hypothesis that the deletion allele of the ACE gene might be associated with increased levels of PAI-1. We related the ACE genotype to PAI-1 antigen levels in 603 men and 221 women attending a routine health screening. As a whole, the plasma PAI-1 level was not strongly associated with ACE genotype. Since the PAI-1 level was significantly influenced by well-known risk factors for coronary artery disease (CAD), we further analyzed the data after excluding subjects with major cardiovascular risk factors. In low-risk male subjects, the DD genotype had significantly higher levels of plasma PAI-1 (DD: 20.3±2.2; DI: 13.9±1.1; II: 13.6±1.3 ng/mL, P=.010 by ANOVA). In low-risk female subjects, the DD genotype showed a tendency to a high level of plasma PAI-1 without statistical significance. When analysis was restricted to postmenopausal women (age
55 or FSH35 ng/mL), the
DD genotype showed a significantly higher level
of PAI-1 than subjects with the DI and II
genotypes (27.7±6.2 versus 15.6±1.8 ng/mL,
P=.028). The DD polymorphism of the ACE gene is
associated with high PAI-1 levels in male and possibly in
postmenopausal female subjects who have lower conventional
cardiovascular risk factors. These results suggest that
the increased ACE activity caused by DD polymorphism may play an
important role in elevating the level of plasma PAI-1. Our data support
the notion that the genetic variation of ACE contributes to the balance
of the fibrinolytic pathway.
Key Words: angiotensin converting enzyme • polymorphism • plasminogen activator inhibitor-1 • renin-angiotensin system
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Introduction |
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The RAS, which is present in the circulating and tissue forms, has been shown to be involved in the pathogenesis of cardiovascular diseases.1 Genes that influence the RAS are potential etiologic candidates for ischemic cardiovascular disease.2,3
A polymorphism of the ACE gene consisting of the insertion or deletion (I/D) of a 287-bp fragment in intron 16 has been described as being strongly associated with the level of circulating enzyme.4 It has been reported that the ACE I/D polymorphism is associated with increased risk for MI, especially among low-risk subjects.5–8 Nevertheless, the pathophysiological mechanism linking the ACE genotype and myocardial infarction remains unknown. However, the findings of Ludwig et al9 that the ACE D allele is not a risk factor for the development of coronary stenosis, but rather that it impacts on the transition of preexisting stenosis to MI, suggest that the mechanism may involve an interaction between the ACE genotype and thrombus formation.10 The balance between thrombogenesis and fibrinolysis is central to the evolution of intravascular thrombosis.
It has been suggested that the ACE gene polymorphism influences Ang II in the peripheral and/or local circulation through its effect on ACE levels in plasma and endothelial cells.11 The DD genotype has been shown to be associated with enhanced conversion of Ang I to Ang II.12
In addition to the well-characterized effects of Ang II on vascular homeostasis, evidence is accumulating to suggest that Ang II also modulates fibrinolysis.10 Recently, in vivo and in vitro studies have shown that Ang II increases PAI-1 mRNA and plasma PAI-1 levels.13–16 For example, infusions of Ang II increased plasma PAI-1 activity in humans.13 Ang II has also been shown to induce PAI-1 expression in vascular endothelial and smooth muscle cells in culture,14–16 and treatment with ACE inhibitors has been shown to lower plasma PAI-1 activity.17 These studies suggest a possible link between the RAS and fibrinolytic function.
Based on the notion that tissue Ang II levels may be increased in patients carrying the D allele and Ang II induces expression of PAI-1, a previous work has suggested that PAI-1 levels may be increased in patients carrying the D allele.15 Recently, a small body of evidence from African–American patients with hypertension has linked the ACE D allele to increased PAI-1 levels.18 However, the number of patients in this study was rather small and the effect of hypertension itself on the association between ACE polymorphism and PAI-1 levels should be ruled out. Two other studies failed to show a relationship between the ACE genotype and PAI-1 levels.19,20
Therefore, in the present study, we tested the hypothesis that the D allele of the ACE gene is associated with increased levels of PAI-1. Since it is well known that PAI-1 levels are influenced by risk factors for CAD,21–24 we analyzed the association according to the presence or absence of coronary risk factors.
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Methods |
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Subjects and Study Design
All subjects in this study were Korean. Subjects with evidence of CAD based on typical angina, positive treadmill test, or findings of MI on ECG were excluded from the study. A total of 824 subjects (603 men and 221 women) attending a routine health screening was recruited to the study, which was approved by the Ethical Committee of Samsung Medical Center. Subjects attended after an overnight fast, and weight and height were recorded. Blood pressure was taken with an automatic sphygmomanometer. Hypertension was defined as systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg on casual blood pressure measurement, by a history of patients taking antihypertensive agents, or by previous diagnosis of hypertension. Diabetes was defined as fasting blood sugar level >125 mg/dL or by a history of patients using oral hypoglycemic agents or insulin. Hypercholesterolemia was defined as total serum cholesterol level
240 mg/dL. Smoking was defined
by a history of smoking in the past 1 year. Obesity was defined by a
body mass index (BMI) 26 kg/m2 (BMI=
body weight [kg]/height [m]2).
Biochemical Methods
Blood samples were collected between 8:00 and 9:00
AM, after an overnight fast, from an antecubital vein with
subjects in the sitting position. For determination of plasma PAI-1
levels, blood was anticoagulated with 3.8% trisodium citrate (9:1,
vol/vol) and kept on crushed ice until
centrifugation and subsequent analysis. The
plasma PAI-1 level was measured by enzyme linked immunoassay kits
(Stago). The intra-assay coefficient of variation in our laboratory was
8.6%. Serum lipids were determined by enzyme
colorimetric methods, and low-density lipoprotein (LDL)
level was calculated by the Friedewald formula. Plasma glucose was
assayed with the hexokinase assay method (Boehringer Mannheim).
Plasma FSH (follicle stimulating hormone) was measured by ACS-180
(Ciba-Corning).
Genetic Analysis
Genomic DNA was amplified as previously described using the PCR
with primers flanking the polymorphic
region.25 PCR products of the two alleles
of 490 and 190 bp were separated on 1.5% agarose gel and visualized by
ethidium bromide staining.
Statistical Analysis
Data were analyzed using the SAS (Statistical
Application System, version 6.10). The levels of the quantitative
variables are presented as the mean±SEM. The variables
were compared among the three genotypic groups by ANOVA followed by a
multiple comparison test. The null hypothesis was that the
ACE genotype was without effect on the PAI-1 level,
and the statistical significance was taken as P<.05.
Stepwise regression analysis was used to estimate the
association of coronary risk factors with plasma PAI-1
level.
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Results |
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ACE Genotype Frequencies
PCR amplification of genomic DNA produced fragments of 490 and/or 190 bp, yielding the genotypes II, DI, and DD, respectively. ACE polymorphism was determined in 824 subjects who had no evidence of CAD. Mean age was 49.7±8.4 years (range 24 to 77 years). The genotype distributions were in Hardy-Weinberg equilibrium (P>.975). The D and I alleles had frequencies of 40.5% and 59.5%, respectively. The frequencies of DD, DI, and II genotypes were 15.8%, 49.5%, and 34.7%, respectively. These allele frequencies were similar to those previously reported for Japanese and Chinese control populations, but different from those reported for the Western control groups (Table 1
). We found no significant differences
among ACE genotypes in BMI, systolic or
diastolic blood pressure, smoking, fasting blood glucose,
or mean lipid levels (data not shown).
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ACE Polymorphism and Plasma PAI-1 Level in All
Subjects
Of the study population, plasma PAI-1 antigen level was measured
simultaneously with ACE polymorphism in 799 subjects
(585 men and 214 women). Plasma PAI-1 levels were 20.0±1.3, 18.8±0.8,
and 18.2±0.9 ng/mL for the DD, DI, and II
genotypes, respectively, as shown in Table 2. The results showed no significant
relationship between ACE genotype and plasma PAI-1
level. Subjects with the DD genotype appeared to
have a higher plasma PAI-1 level than those with the DI or
II genotypes. However, there was no statistical
significance in this finding.
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Coronary Risk Factors and Plasma PAI-1 Level
The plasma PAI-1 level was significantly influenced by
coronary risk factors such as
hypercholesterolemia, diabetes, hypertension,
smoking, and obesity (Table 3). Stepwise
regression analysis using these factors as independent
variables showed that hypercholesterolemia,
hypertension, smoking, and obesity correlated with PAI-1 levels.
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ACE Polymorphism and PAI-1 Level in Subjects Without Major
Coronary Risk Factors
Since the PAI-1 level was significantly influenced by well-known
risk factors for CAD, we restricted the analysis to subjects
without major coronary risk factors, such as
hypercholesterolemia, diabetes, hypertension,
smoking, or obesity. A total of 291 subjects (176 men and 115 women)
was included in this analysis (Table 4 and Fig. 1). The frequencies of the DD,
DI, and II genotypes were 16.2%, 50.9%, and
33.0%, respectively, and the D and I alleles had frequencies of
41.6% and 58.4%, respectively. The results showed that among subjects
without major coronary risk factors, the plasma PAI-1 antigen
level was significantly higher in subjects with the DD
genotype, especially if these subjects were male. The plasma
PAI-1 level also tended to be high in female subjects with the
DD genotype, but this tendency was not statistically
significant.
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In view of the association between ACE genotype and
PAI-1 level, coronary risk factors potentially related to the
PAI-level were compared in low-risk male subjects from the three groups
of ACE genotypes. As shown in Table 5, no difference could be detected
between the genotypes for total cholesterol, blood
glucose, systolic blood pressure, diastolic blood
pressure, or smoking, but there was an effect on BMI. Stepwise
regression analysis yielded BMI and ACE
genotype as the factors significantly related to PAI-1 levels
in this group (R2 values, 0.05 and 0.08;
P values, .001 and .005 for BMI and ACE
genotype, respectively).
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We also analyzed the relationship between PAI-1 level and ACE genotype in subjects with major coronary risk factors. In subgroups with hypertension, hypercholesterolemia, diabetes, obesity, and smoking, there was no association between ACE polymorphism and the PAI-1 level (P>.05 by ANOVA) (data not shown).
ACE Polymorphism and PAI-1 Level in Female Subjects Without
Major Coronary Risk Factors
In view of the fact that the plasma PAI-1 level is influenced by
the estrogen level, we further analyzed the association of
PAI-1 level and ACE genotype in subgroups of women
according to their menopausal status (Table 6). Women whose ages were equal to or
greater than 55 years or where serum FSH levels were equal to or
greater than 35 ng/mL were considered to be in menopause.
Although the number of study subjects was small, the greatest
difference in PAI-1 level between postmenopausal and premenopausal
women was observed in the DD genotype. In
premenopausal females, there was no difference in PAI-1 levels between
the ACE genotypes. When we analyzed
postmenopausal women, the DD genotype showed
significantly higher plasma PAI-1 levels compared with either the
DI genotype or the DI and II
genotypes combined.
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Discussion |
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The present report examines the relationship between ACE I/D polymorphism and fibrinolytic potential in a large number of subjects and in subgroups defined by the presence or absence of coronary risk factors. Although PAI-1 levels were not significantly different among ACE genotypes in the entire group, the DD genotype gave a significantly higher PAI-1 level in men and possibly in postmenopausal women who were at low risk for CAD. This observation may be extended to provide a link between this genetic variant and the fibrinolytic pathway.
The overall genotype and allele frequencies observed in our study are similar to those observed in other Asian populations, but are different from those reported from Western countries. The current study supports previous contentions that the frequency of the ACE genotype varies depending on ethnic origin.29 Our findings, that risk factors for CAD are related to PAI-1 levels, are also consistent with previous reports.21–24
The D allele of ACE I/D polymorphism is co-dominantly associated with the mean immunoreactive level and activity of plasma ACE, that is, levels are higher in homozygotes for the D allele than in homozygotes for the I allele, and are intermediate in heterozygotes (ACE levels are DD>DI>II).4 ACE appears to influence the cardiovascular system at many sites and in multiple ways.30,31 Evidence for deleterious cardiovascular effects mediated through ACE emerges from several studies,32–34 although the mechanism remains unclear.
Several studies have suggested that in vivo increases in local ACE activity result in parallel increases in tissue Ang I conversion to Ang II, with corresponding changes in local function.35–37 These data suggest that local tissue ACE may be a rate-limiting factor in regulating local Ang II production. In fact, the DD genotype has been shown to be associated with the enhanced conversion of Ang I to Ang II.12
Data are now available supporting the view that the RAS plays a role in the regulation of fibrinolytic balance.10 Ang II has been shown to induce PAI-1 expression in vascular endothelial and smooth muscle cells in culture.14–16 More recent data indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1.38 In vivo studies have confirmed the relevance of these in vitro findings. Infusions of Ang II cause an acute dose-related rise in PAI-1 antigen in both normotensive and hypertensive subjects.13 In another in vivo study, treatment with ACE inhibitors lowered plasma PAI-1 activity.17 Very recently, an experimental study showed that ACE inhibitors not only reduce the basal expression of PAI-1 but also inhibit the induction of PAI-1 mRNA in rat aorta after balloon injury, demonstrating that Ang II regulates PAI-1 expression of the arterial wall.39 These studies suggest a potential link between the RAS and fibrinolytic function.
PAI-1 is synthesized by the endothelium, vascular smooth muscle cells, and other cells. It is present in these cells, the extracellular matrix, and in the plasma where the majority of PAI-1 is active.40 PAI-1 has a rapid action and is a specific inhibitor of plasminogen activators, both of tissue type (tPA) and of urokinase type (uPA), and it regulates plasminogen activation in vivo.40 Impaired endogenous fibrinolysis by PAI-1 is associated with an increased risk of intravascular thrombosis. Increased levels of PAI-1 have been found in patients with angina and MI.41–43
Given the importance of thrombosis in coronary heart disease, it is tempting to speculate that subjects with the DD genotype have higher tissue ACE levels than those with other genotypes. It could also be suggested that the increased local production of Ang II induces increased production of PAI-1, which in turn leads to an increased risk of MI through increased thrombosis or impaired fibrinolysis.
The present study demonstrates that the homozygous deletion genotype of the ACE gene was associated with an increased level of PAI-1 in low-risk male subjects and possibly in postmenopausal female subjects. As we have shown, plasma levels of PAI-1 are also influenced by many other coronary risk factors. In addition to the ACE I/D polymorphism, stepwise regression analysis showed that CAD risk factors, such as hypercholesterolemia, hypertension, smoking, and obesity, also influenced PAI-1 levels. This may explain why the relationship between PAI-1 and ACE I/D polymorphism is significant after the removal of interference by other influencing factors. Mattu et al8 and Gardemann et al44 reported that the DD genotype was associated with CAD only in low-risk patients. Cambien et al5 also reported that the ACE I/D polymorphism was associated with MI, particularly in the subgroup with low cardiovascular risk. This association between the DD genotype and CAD in low-risk patients may be explained by the increased levels of PAI-1 observed in our study.
Although no previous studies directly investigated the association between ACE gene polymorphism and PAI-1 level in postmenopausal female subjects, there are reports showing that subjects with a low estrogen status have a lower fibrinolytic potential (higher PAI-1 levels) than subjects with a high estrogen status.45 Although the number of postmenopausal women with the DD genotype is small, our results clearly suggest that postmenopausal women with the DD genotype have a higher level of PAI-1 than those with the DI or II genotype. Our results also show that the greatest difference in PAI-1 level between postmenopausal and premenopausal women is observed in the DD genotype. Therefore, these findings indicate that the cardioprotective effect of estrogen may be greater in postmenopausal women with the DD genotype. However, further studies with a larger number of subjects are needed to substantiate the above notions.
The PAI-1 level in the II genotype did not differ from that in the DI genotype. This finding contrasts with earlier findings that plasma ACE activity was lowest in subjects with the II genotype. Our observation is, however, comparable to observations of Costerousse et al46 in human T lymphocytes and of Danser et al47 in the human heart, which found the highest tissue ACE activity in the DD genotype, but no difference in ACE activity between the DI and II genotypes. It has been suggested that the absence of a gene dosage effect in tissue may be due to unknown genetic or environmental effects.
Our data contrast with observations in the English Diabetic Study, which showed similar trends of increased PAI-1 activity in the ACE DD genotype but without statistical significance.20 However, they did not further analyze the subgroups based on cardiovascular risk factors or on menopausal state. A preliminary study suggested that PAI-1 antigen levels are increased in medically treated hypertensive African–American patients who have the ACE D allele.18 Margaglione et al19 have analyzed the relationship between the ACE I/D and PAI-1 4G/5G polymorphisms and their effects on PAI-1 antigen levels. For all PAI-1 genotypes, the DD genotype was associated with a nonsignificant 10% to 30% increase in plasma PAI-1 levels compared to the II genotype. The number of subjects in these studies was small, and, certainly, a larger study is needed to investigate possible links between the ACE I/D genotype and PAI-1 levels.
In conclusion, our study showed that the I/D polymorphism of the ACE gene is associated with PAI-1 levels in male and possibly in postmenopausal female subjects without conventional CAD risks. The results of the present study suggest that elevation of ACE activity in the DD genotype may have increased the plasma PAI-1 level. ACE I/D polymorphism may identify a genetic variant that contributes to increased thrombosis by way of impaired fibrinolysis. Given the potential importance of the link between increased PAI-1 levels and the D allele of the ACE gene, further studies are needed to complement our preliminary observation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from the Science and Technology Policy Institute (B-02-04-02), the Samsung Biomedical Research Institute (C-95-003-02), and the Samsung Medical Center.
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Footnotes |
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Cardiovascular Institute (D.-K.K., H.-C.K., J.-C.R., J.-A.C., Y.C., W.-R.L.), Department of Medicine (C.-H.R.), Department of Clinical Pathology (J.-W.K.), Samsung Medical Center; and Center for Clinical Research (D.-K.K., S.K., J.-E.H.), Samsung Biomedical Research Institute, Sung Kyun Kwan University, College of Medicine, Seoul, Korea.
Received April 4, 1997; accepted July 25, 1997.
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