© 2001 American Heart Association, Inc.
Thrombosis |
Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen
From the Divisions of Clinical Pharmacology (N.J.B., L.J.M.) and Cardiovascular Medicine (D.E.V.), Vanderbilt University Medical Center, and the Veterans Administration Medical Center (D.E.V.), Nashville, Tenn; and the Endocrine Hypertension Division, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass (N.S., N.K., G.H.W.).
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Abstract |
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Abstract—Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased circulating PAI-1 antigen and increased risk of thrombotic cardiovascular events. A 4G/5G polymorphism located 675 bp upstream from the transcription start site of the PAI-1 gene affects PAI-1 antigen concentrations. To test the hypothesis that PAI-1 4G/5G genotype influences the effect of activation of the RAAS on PAI-1 expression, we measured morning PAI-1 antigen concentrations in 76 subjects with essential hypertension during low (10 mmol/d) and high (200 mmol/d) salt intake. Low salt intake was associated with activation of the RAAS as measured by plasma renin activity (2.3±0.2 versus 0.5±0.0 ng angiotensin I · mL-1 · h-1, P<0.001) and aldosterone (529±40 versus 145±12 pmol/L). PAI-1 antigen concentrations were 17.9±2.7, 19.2±2.5, and 27.8±4.0 ng/mL during high salt intake and 19.2±2.7, 21.6±2.9, and 38.9±7.2 ng/mL during low salt intake in the 5G/5G (n=14), 4G/5G (n=40), and 4G/4G (n=22) groups, respectively. There was a significant effect of both salt intake (F=6.0, P=0.017) and PAI-1 4G/5G genotype (F=7.6, P=0.001) on PAI-1 antigen. More importantly, there was a significant interactive effect (F=7.8, P=0.001) of salt intake and PAI-1 4G/5G genotype on PAI-1 antigen. PAI-1 4G/5G genotype influenced the relationship between serum triglycerides and PAI-1 antigen such that the relationship was significant only in 4G homozygotes during either high (R2=0.31, P=0.014) or low (R2=0.37, P=0.006) salt intake. This study identifies an important gene-by-environment interaction that may influence cardiovascular morbidity and the response to pharmacological therapies that interrupt the RAAS.
Key Words: thrombosis • genetics • fibrinolysis • coagulation
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Activation of the renin-angiotensin-aldosterone (RAAS) system has been associated with an increased risk of myocardial infarction (MI) and stroke in patients with essential hypertension.1 2 Conversely, interruption of the RAAS by ACE inhibition reduces the risk of MI in patients at risk for coronary artery disease.3 Recent studies suggest that the effects of activation and interruption of the RAAS on cardiovascular morbidity and mortality derive in part from an interaction of the RAAS and fibrinolytic systems.4 5
Endogenous fibrinolysis plays a critical role in limiting thrombosis and depends on the balance between plasminogen activators (primarily tissue plasminogen activator, tPA) and plasminogen activator inhibitors (PAI, predominantly PAI-1).6 7 Both of these essential fibrinolytic components are synthesized locally in the vascular wall (in endothelial and smooth muscle cells), have short half-lives, and circulate in trace concentrations in the plasma. Increased PAI-1 expression has been demonstrated in atherosclerotic lesions.8 9 Elevated PAI-1 concentrations are seen in youthful survivors of acute MI compared with age-matched control subjects,10 and elevated levels of PAI-1 appear to be a risk factor for recurrent MI.11 PAI-1 antigen and activity are increased in patients with insulin resistance and may contribute to the increased mortality due to cardiovascular disease in this group.12 Our group and others have shown that angiotensin (Ang) II and aldosterone stimulate PAI-1 expression, whereas ACE inhibition decreases PAI-1 both in vitro and in vivo.4 5 13 14 15
A common single 4/5 guanine (4G/5G) polymorphism located 675 bp upstream from the transcription start site of the PAI-1 gene that influences PAI-1 production has been described.16 PAI-1 antigen and activity are highest in individuals who are homozygous for the 4G allele and lowest in those homozygous for the 5G allele. In case-control studies, the prevalence of the 4G allele is significantly higher in young patients with MI than in population-based control subjects,17 although studies in older patients have not uniformly confirmed an association between PAI-1 4G/5G genotype and coronary thrombotic events.18 19 20 The mechanism underlying allelic differences in PAI-1 production has been explained by the observation that both the 4G and 5G alleles bind a transcriptional activator, whereas the 5G allele also binds a transcriptional repressor.17 Therefore, in the absence of the bound repressor, the basal level of PAI-1 transcription is increased. Furthermore, studies using reporter constructs have shown that the 4G allele produces 6 times more mRNA than the 5G allele in response to interleukin-1.21
Studies in patients with insulin resistance suggest that PAI-1 4G/5G genotype influences the relationship between triglycerides and PAI-1 expression.22 Furthermore, there is a concentration-response relationship between glucose and plasma PAI-1 in 4G/4G homozygotes.22 The present study tests the hypothesis that the PAI-1 4G/5G polymorphism also modulates the effect of activation of the RAAS on PAI-1 expression in patients with essential hypertension.
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Methods |
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Subjects
Subjects with essential hypertension were studied. Informed consent was obtained, and the study was approved by the Brigham and Women’s Hospital Institutional Review Board and conducted according to the Declaration of Helsinki. Each subject underwent a history, physical examination, ECG, and laboratory analysis. Subjects were defined as hypertensive if they had a diastolic blood pressure of
90 mm Hg and had had
hypertension for 6 months. Patients with secondary forms of
hypertension, diabetes mellitus, renal insufficiency, or any
significant medical illness were excluded. ACE inhibitors
were discontinued for 3 weeks and all other antihypertensive
medications were discontinued for 2 weeks before initiation of the
study protocol.
General Protocol
All subjects participated in a protocol designed to
phenotype them according to their response to exogenous Ang II,
described in detail
elsewhere.23 In brief,
subjects were supplied a caffeine- and alcohol-free diet providing a
daily intake of 200 mmol sodium (high salt), 100 mmol
potassium, 800 mg calcium, and 200 to 300 g carbohydrate for 7
days. Blood was obtained on the morning of day 5 for measurement of
fasting insulin, glucose, cholesterol, and
triglycerides. On the morning of day 8, blood was drawn
through an indwelling catheter for measurement of plasma renin activity
(PRA), aldosterone, Ang II, cortisol, and PAI-1 antigen
after the subject had fasted overnight and had remained supine for 1
hour. Blood was also obtained for extraction of genomic DNA. Subjects
were then given intravenous infusions of
para-aminohippurate for measurement of renal blood flow and Ang II as
previously described.23
After completion of the high-salt diet, subjects were provided a
low-salt (10 mmol/d) diet for an additional 7 days. Dietary
potassium, calcium, and carbohydrate intake were held constant. Fasting
insulin and glucose concentration measurements were repeated on day 5
of the diet. In addition, PRA and aldosterone
concentrations were measured through an indwelling catheter after each
subject had been supine for 1 hour and after 2 hours of ambulation. On
day 7, blood was again obtained for measurement of PRA,
aldosterone, Ang II, cortisol, PAI-1, and tPA antigen
before para-aminohippurate and Ang II infusions. Dietary compliance was
assessed by 24-hour urine collection at the end of each diet
period.
Laboratory Analysis
All supine samples were collected between 8:00 and
9:00 AM. Blood samples were
collected in chilled tubes and immediately centrifuged at 0°C
at 3000 RPM for 20 minutes; plasma was then stored at -70°C until
the time of assay. Blood for measurement of PAI-1 and tPA antigen was
collected in chilled tubes containing 0.105 mol/L sodium citrate, and
antigen levels were determined with a 2-site ELISA (Biopool AB) as
previously described. In 54 subjects (11 5G/5G, 31 4G/5G, 12
4G/4G), plasma obtained during low salt intake was also assayed for tPA
antigen by 2-site ELISA (Biopool AB). Blood for PRA and Ang II was
collected in chilled tubes containing EDTA. PRA was determined by
radioimmunoassay measurement of Ang I generated at 37°C, pH 6.0
(INCSTAR Corp). Ang II was measured in 38 of 76 subjects (6 5G/5G, 18
4G/5G, 14 4G/4G). Urea (4 mmol/L) was added to plasma samples
before freezing to block the formation or degradation of Ang II, and
Ang II was measured by high-performance liquid
chromatography as previously
described.24 Serum
aldosterone (Diagnostic Corp) and cortisol
(INCSTAR Corp) levels were assayed with commercially available
radioimmunoassay kits. Glucose and insulin were measured by
colorimetry (Johnson & Johnson Clinical
Diagnostics) and radioimmunoassay (Tosoh Medics, Inc),
respectively. Sodium and potassium were measured by direct
potentiometry with an ion-selective electrode (NOVA Analyzer I,
NOVA Biochemical). Creatinine was measured with a Beckman
model II creatinine analyzer.
PAI-1 4G/5G Genotyping
A commercially available process (Qiagen Inc) was
used for the extraction of DNA from EDTA-anticoagulated blood. The
PAI-1 4G/5G polymorphism
was genotyped with a 25-µL mixture containing standard
polymerase chain reaction (PCR) buffer, 10 mmol/L dNTP, 4 µmol/L
primers, 0.4 U Taq polymerase,
and 25 ng genomic DNA and previously published primers,
5'-CACAGAGAGAGTCTGGCCACGT-3' and
5'-CCAACAGAGGACTC-TTGGTCT-3'. The upstream primer
was modified by substituting a cytosine for adenine at position
-681, thereby introducing a
BslI restriction site in the
presence of the 5G but not the 4G allele. After
BslI digestion for 2.5 hours at
55°C, PCR products were separated on a 3% agarose gel, stained
with ethidium bromide, and visualized under ultraviolet light. The 4G
allele corresponded to the presence of an uncut 98-bp product
and the 5G allele to 77- and 22-bp fragments. A DNA sample known to
be heterozygous for 4G/5G was used as a control.
Statistical Analysis
Data are presented as mean±SEM. The effect
of salt intake on specific endocrine or fibrinolytic variables was
determined with a paired Student’s
t test.
PAI-1 genotype
frequencies were compared with expected frequencies by
2 analysis. The effect of
PAI-1 genotype on
endocrine or fibrinolytic variables was determined by 1-way ANOVA
followed by Bonferroni’s test. The interactive effect of salt intake
and PAI-1 genotype on
PAI-1 antigen was assessed by repeated-measures ANOVA in which the
within-subject variable was salt intake and the between-subject
variable was PAI-1
genotype. Pearson’s or Spearman’s correlation coefficients
were used to examine simple relationships among variables, as
appropriate. Multiple linear regression analysis was carried
out to evaluate the possibility of interactions among variables
affecting PAI-1 antigen. In the model,
PAI-1 4G/5G genotype
was coded by dummy variables as follows: PAI-1 4G/4G was 1 for
4G/4G individuals and 0 for 4G/5G and 5G/5G individuals; PAI-1 5G/5G
was 1 for 5G/5G individuals and 0 for 4G/5G and 4G/4G individuals. A
value of P<0.05 was considered
statistically significant.
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Results |
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Seventy-six subjects with essential hypertension were studied under both high- and low-salt conditions. Subject characteristics appear in Table 1
. Sixty-eight of the 76 subjects were classified as
normal-to-high renin, as defined by an upright PRA of 2.4 ng Ang I
· mL-1 ·
h-1 during low salt intake. The
distribution of PAI-1 4G/5G
genotypes (18% 5G/5G, 53% 4G/5G, and 29% 4G/4G) was in
Hardy-Weinberg equilibrium.
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Effect of Salt Intake and
PAI-1 Genotype on
Blood-Pressure and Endocrine Parameters
Table 2 provides blood-pressure, endocrine, and
fibrinolytic data for subjects under conditions of high and low salt
intake. Twenty-four-hour urinary sodium excretion was significantly
lower during low salt intake than during high salt intake, whereas
potassium excretion was higher. Systolic and
diastolic blood pressures were significantly lower during
low than during high salt intake. PRA, aldosterone, and
cortisol concentrations were significantly increased during low salt
intake compared with those measured during high salt intake. There was
no effect of salt intake on Ang II, fasting insulin, or glucose
concentrations.
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There was a significant relationship between
PAI-1 4G/5G genotype
and serum cortisol concentration under high-salt conditions
(P=0.003,
Table 3), but not under low-salt conditions. Fasting plasma
glucose concentration measured under high-salt conditions also differed
significantly among genotype groups
(P=0.04). There was no
relationship between PAI-1
4G/5G genotype and body mass index, serum
triglycerides, insulin, systolic or
diastolic blood pressure, or any other endocrine
parameter.
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Effect of Salt Intake and PAI-1
Genotype on Fibrinolytic Parameters
Figure 1 illustrates the relationship between
PAI-1 4G/5G genotype
and PAI-1 antigen concentrations under high- and low-salt conditions.
PAI-1 antigen measured during high salt intake correlated with that
measured during low salt intake
(R2=0.05,
P<0.001). Under either salt
condition, PAI-1 antigen concentrations were highest in subjects
homozygous for the 4G allele and lowest in those homozygous for the
5G allele
(Table 3
) (F=7.6,
P=0.001 for effect of
genotype by ANOVA). Overall, low salt intake was associated
with an increased PAI-1 concentration compared with high salt intake
(Figure 1; F=6.0,
P=0.017 for effect of salt by
ANOVA). When subjects were stratified according to
PAI-1 4G/5G genotype,
however, the effect of salt on PAI-1 antigen concentrations was
significant only in subjects who were homozygous for the 4G allele
(F=7.8, P=0.001 for salt x
PAI-1 genotype
interaction by ANOVA). Under low-salt conditions, there was no effect
of PAI-1 4G/5G genotype
on tPA antigen; thus, the molar ratio of PAI-1 to tPA increased with
increasing numbers of 4G alleles
(Table 3).
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P=0.017 vs 5G/5G during low salt, 
P=0.038 vs 4G/4G during high salt intake.
PAI-1 antigen, measured during either high or low salt
intake, correlated with PAI-1
4G/5G genotype, body mass index, systolic blood
pressure, plasma triglycerides, fasting glucose, fasting
insulin, and PRA and aldosterone measured under
salt-replete conditions
(Tables 4 and 5). During low salt intake, PAI-1 antigen also
correlated with PRA and diastolic blood pressure. There was
no relationship between PAI-1 antigen and age, sex, ethnicity, Ang II,
urine potassium excretion, or cortisol under either high- or low-salt
conditions. In multivariate regression models, body
mass index and PAI-1
4G/4G genotype predicted PAI-1 antigen measured under either
high-salt or low-salt conditions
(Table 6). Under low-salt conditions, salt-replete
aldosterone also predicted plasma PAI-1 antigen, whereas
PRA and insulin predicted PAI-1 antigen under high-salt
conditions.
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To test the hypothesis that
PAI-1 4G/5G genotype
influences the relationship between triglycerides and
circulating PAI-1 antigen concentrations in subjects with essential
hypertension, we examined the relationship between PAI-1 antigen
concentrations and triglycerides under both low- and
high-salt conditions. Under both high-salt
(R2=0.31,
P=0.014) and low-salt
(R2=0.37,
P=0.006) conditions, PAI-1
antigen correlated with serum triglycerides in individuals
homozygous for the PAI-1 4G
allele, but not in those homozygous for the 5G allele or
in heterozygotes
(Figure 2). Under low-salt conditions, there appeared to be 2
subsets of data for the relationship between serum
triglycerides and PAI-1 antigen in heterozygous subjects.
These apparent subsets, however, were not defined by renin status, sex,
ethnicity, or quartiles of body mass index, blood pressure, glucose,
insulin, aldosterone, or Ang II. In 4G/4G subjects, the
relationship between triglycerides and PAI-1 antigen
observed during low salt intake was similar to that observed during
high salt intake (P=0.19 for
the comparison of the slopes of the
lines).
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Discussion |
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Activation of the RAAS by either salt depletion or diuretic treatment results in increased circulating PAI-1 antigen concentrations in healthy volunteers.5 25 The present study extends this observation to subjects with essential hypertension. More importantly, the study indicates that the 4G/5G polymorphism, located at -675 bp of the PAI-1 promoter, influences the effect of activation of the RAAS by salt depletion on circulating PAI-1 concentrations.
The finding that 4G/5G genotype modulates the effect of activation of the RAAS on circulating PAI-1 antigen concentrations has important implications for clinical studies. For example, ACE inhibitors have been found to reduce PAI-1 antigen concentrations in many,5 26 27 28 29 30 but not all, studies.31 32 The present data suggest that the effect of ACE inhibition on PAI-1 antigen concentrations and fibrinolytic balance may depend on the PAI-1 4G/5G genotype frequencies in the population studied. On the basis of the finding that salt depletion caused the greatest increase in PAI-1 antigen in 4G/4G subjects, the effect of ACE inhibition on circulating PAI-1 antigen would be expected to be greatest in individuals homozygous for the 4G allele.
Conversely, the results of this study suggest that activity of the RAAS influences the relationship between PAI-1 4G/5G genotype and PAI-1 antigen concentrations. Thus, the relationship between 4G/5G genotype and circulating PAI-1 antigen concentrations was attenuated under high-salt conditions, when PRA and aldosterone are suppressed, compared with under low-salt conditions. Given that renin activity decreases with age,33 the finding that activation of the RAAS accentuates the relationship between the PAI-1 genotype and PAI-1 antigen concentrations may explain the observed association between PAI-1 4G/5G genotype and MI in young,10 but not older,19 20 populations. Although there was no relationship between age and PAI-1 antigen concentrations in the present study, the study population was relatively young, and all but 8 subjects had normal to high PRA.
This study does not specifically address the mechanism for the interactive effect of PAI-1 genotype and salt intake on PAI-1 antigen. Salt depletion was associated with activation of the RAAS, as measured by both PRA and aldosterone concentrations. Although plasma Ang II concentrations were not increased during low salt intake, this finding may reflect the relatively small number of subjects in whom Ang II was measured or difficulties in accurately measuring Ang II because of its short half-life.34 We have previously observed that PAI-1 antigen concentrations correlate with PRA and aldosterone concentrations in normotensive subjects.5 In the present study, PAI-1 antigen correlated with PRA and aldosterone under high-salt conditions and with PRA alone under low-salt conditions. Although mean cortisol concentration was higher during low salt intake than during high salt intake and serum cortisol concentration increased with the number of PAI-1 4G alleles under high-salt conditions, there was no correlation between cortisol and PAI-1 antigen under either low- or high-salt conditions.
Both Ang II (or its hexapeptide metabolite, Ang IV) and aldosterone increase PAI-1 expression in a variety of cell types, including astrocytes,35 endothelial cells,4 vascular smooth muscle cells,36 proximal tubular epithelial cells,37 and mesangial cells.38 Systemic infusion of Ang II increases vascular, renal, and hepatic PAI-1 expression in rats,39 whereas treatment of animals with ACE inhibitors, AT1 receptor antagonists, or aldosterone receptor antagonists decreases tissue PAI-1 expression.15 40 Ang II stimulates PAI-1 expression through a serum-inducible element localized to a sequence between -47 and -38 bp in the PAI-1 promoter.41 Functional studies suggest the presence of 2 steroid-responsive elements in the PAI-1 promoter: one between -64 and -59 bp and a second farther upstream.42 Additional studies are needed to examine how the binding of transcription activators and repressors at the -675 PAI-1 4G/5G locus might influence Ang II– and aldosterone-induced PAI-1 expression.
Studies of the relationship between blood pressure and fibrinolytic balance may be confounded by the association of hypertension with insulin resistance. Two large cohort studies, however, suggest an independent association between blood pressure and PAI-1.43 44 In the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study of 1558 men and women, high PAI-1 activity correlated with diastolic blood pressure in men, but not women, after control for anthropomorphic characteristics and lipid levels.43 In a study of the Framingham Offspring Population, PAI-1 activity correlated with systolic and diastolic blood pressure in 1193 men and 1459 women, even after control for triglycerides, body mass index, and diabetes.44 In the present study, PAI-1 activity correlated with systolic blood pressure during both low and high salt intake, but this correlation was no longer significant after adjustment for triglycerides or body mass index. The lack of association between blood pressure and PAI-1 in the adjusted analysis may reflect the small sample size compared with the previous cohort studies as well as the substantial effect of insulin resistance on PAI-1.
Previous studies have demonstrated that
PAI-1 4G/5G genotype
influences the relationship between serum triglycerides and
PAI-1 antigen in diabetic patients, such that triglycerides
and PAI-1 antigen correlate in individuals who are homozygous for the
4G allele but not in individuals who carry 1 copy of the 5G
allele.22 This
genotype-specific effect of triglycerides has been
attributed to the interaction of the
PAI-1 4G/5G site and an
adjacent VLDL triglyceride–sensitive site in the promoter
region of the PAI-1
gene.45 In this study, we
observed a similar genotype-specific effect of
triglycerides on PAI-1 antigen in nondiabetic subjects with
essential hypertension. Significantly, salt intake did not alter the
interactive effect of PAI-1
4G/5G genotype and triglycerides on PAI-1 antigen
concentrations, consistent with a localized interaction between
the 4G/5G locus and VLDL-responsive element.
In summary, previous studies demonstrate that activation of RAAS is associated with both increased PAI-1 antigen concentrations and increased risk of thrombotic cardiovascular events. The present study indicates that genetic variation at the PAI-1 4G/5G locus modulates the effect of activation of the RAAS by salt depletion on circulating PAI-1 antigen concentrations. The study identifies an important gene-by-environment interaction that may influence both cardiovascular morbidity and the response to pharmacological approaches that interrupt the RAAS.
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Acknowledgments |
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This research was supported by the following National Institutes of Health grants: HL-04445, HL-65193, HL-60906, M01-RR-02635 (the Brigham and Women’s Hospital’s General Clinical Research Center), HL-47651, HL-59424, and HL-55000. We thank Ming Su, Qin Hao, Lynne Braley, Beverly Potter, Judy Everett, and Jennifer Bowen for technical assistance.
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Footnotes |
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Reprint requests to Nancy J. Brown, MD, 560 RRB, Vanderbilt University Medical Center, Nashville, TN 37232-6602.
Received February 7, 2001; accepted March 9, 2001.
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