© 1997 American Heart Association, Inc.
Articles |
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
From the Divisions of Cardiovascular and Genetic Epidemiology, Institute of Environmental Medicine, The Karolinska Institute, Stockholm, Sweden (Y.H., N.L.P., U.d.F.); the Division of Cardiovascular Medicine, Department of Medicine (Y.H., U.d.F.) and the Department of Clinical Chemistry (N.E.), Karolinska Hospital, Stockholm, Sweden; and the Center for Development and Health Genetics, College of Health and Human Development, the Pennsylvania State University, University Park, Pa.
Correspondence to Dr Yuling Hong, Divisions of Cardiovascular and Genetic Epidemiology, Institute of Environmental Medicine, Box 210, Doktorsringen 16C, The Karolinska Institute, 171 77 Stockholm, Sweden. E-mail yuling{at}wubios.wustl.edu
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Abstract |
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Abstract Both genes and environmental factors have been reported to influence plasma levels of plasminogen activator inhibitor-1 (PAI-1). However, the relative importance of genetic influences (ie, heritability) on plasma PAI-1 levels has not yet been investigated. Furthermore, PAI-1 levels are correlated with body mass index (BMI) and triglycerides. These correlations could reflect genetic and/or environmental factors in common to PAI-1, triglycerides, and BMI. We applied multivariate genetic analysis methods to assess the relative importance of genetic and environmental influences on plasma PAI-1 levels and to test the significance of genetic and/or environmental influences shared by PAI-1, triglycerides, and BMI in 217 pairs of middle-aged and elderly twins, of whom 113 pairs were reared apart and 121 pairs were women. The heritability estimate for PAI-1 levels was 42%. Individual-specific environmental factors explained 36% of the variance for PAI-1 levels. The remaining variance of PAI-1 was explained by rearing and residual-familial environmental factors. Furthermore, a genetic correlation of 1.00 between PAI-1 and triglycerides, a rearing environmental correlation of 1.00 between PAI-1 and BMI, a residual-familial environmental correlation of 1.00 between PAI-1 and triglycerides, and a genetic correlation of 0.63 between PAI-1 and BMI, were found. In conclusion, the present results suggest that genetic influences on plasma PAI-1 are moderate. Genetic and shared rearing or residual-familial environmental factors shared by PAI-1, BMI, and triglycerides explain the phenotypic association between these measures. It appears that all the genetic influences for PAI-1 are more or less shared with those for triglycerides and BMI.
Key Words: genetic correlations • plasminogen activator inhibitor-1 • heritability • triglycerides • body mass index
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Introduction |
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Increased levels of PAI-1, the main inhibitor of tissue plasminogen activator,1 have been demonstrated in young survivors of acute myocardial infarction,2 in patients with deep vein thrombosis,3 in subjects with asymptomatic carotid artery atherosclerosis,4 in patients with diabetes,5 and in atherosclerotic plaques.6 Accumulated evidence also suggests that increased levels of PAI-1 predict recurrence of myocardial infarction and peripheral atherosclerosis.7–9
A large number of studies have explored the mechanisms regulating plasma PAI-1 levels. In 1986, the full-length human cDNA for PAI-1 was first isolated.10 One year later, the PAI-1 gene was assigned to chromosome 7 (q21.3.q22).11,12 Several polymorphisms in the PAI-1 gene including a HindIII polymorphism,13 a (C-A)n dinucleotid repeat polymorphism,13 and a sequence length polymorphism (4G/5G)14 have been found to be significantly correlated with the plasma levels of PAI-1. Aggregation of elevated PAI-1 levels within family members has also been reported.15,16 It is unlikely that individual differences in plasma PAI-1 levels could be entirely explained by genes. Both environmental factors and gene polymorphisms are involved in the regulation of plasma levels of PAI-1.17 However, the relative importance of genetic (ie, the heritability) and environmental influences on variability in plasma PAI-1 levels has not yet been evaluated. The present study, combining twin and adoption designs, makes it possible to partition the relative contributions of environmental and genetic influences on PAI-1 more accurately.
In the past decade, PAI-1 has also been found to be associated with other cardiovascular risk factors, especially with triglycerides and BMI levels.18 Possible causal associations between PAI-1 and triglycerides in vitro19,20 have been indicated in several studies. However, results from experimental studies in vivo regarding these causal associations have been controversial.21 Obesity may play a role in increased levels of plasma PAI-1,22 and PAI-1 may represent a potential pathogenic link between obesity and cardiovascular disease,23 but no causal association between obesity and PAI-1 has been demonstrated. Hence, mechanisms for these associations have yet to be established. From a family study, Glueck et al24 found that fibrinolysis and hyperlipidemia are influenced to some degree by the same familial factors. They did not, however, try to separate or estimate genetic influences from familial environmental influences. Furthermore, tests of significance of genetic and environmental influences in common to PAI-1 and BMI have not been reported previously.
With the aid of recent developments in biometric analyses, multivariate quantitative genetic methods were applied in the present study to evaluate the extent to which genetic and environmental influences may be shared by PAI-1, triglycerides, and BMI.
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Methods |
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Study Subjects
The present sample is part of the SATSA. The sampling of SATSA twins has been described elsewhere.25,26 The data for the current analyses were collected during the third wave of in-person testing (1992 to 1994). Data were available for BMI in 490 twin individuals, for PAI-1 in 475 twin individuals, and for triglycerides in 463 twin individuals. PAI-1 levels were treated as missing in 14 twin individuals with anticoagulation medications. Twenty-seven twin individuals whose partners did not have PAI-1 measurements were excluded in the genetic analyses, resulting in 434 twin individuals (217 twin pairs), of whom 121 pairs were women. Twenty-nine pairs were monozygotic (MZ) twins reared apart (MZA), 51 pairs were MZ twins reared together (MZT), 74 pairs were dizygotic (DZ) twins reared apart (DZA), and 63 pairs were DZ twins reared together (DZT) as determined by serologic analyses. The mean age of the entire sample was 68 years, ranging from 50 to 85 years.
This study was approved by the Ethics Committee of the Karolinska Institute and the Swedish National Data Inspection Authority. All subjects gave informed consent.
Measurements
Fasting blood samples were taken for determinations of PAI-1 and
triglycerides. Most blood samples were taken in
the morning. Timing of blood sample-taking was independent of zygosity
and rearing situation of the twins. Citrate plasma and serum
samples were extracted and stored at -75°C before the assays
were performed.
PAI-1
A chromogenic assay for PAI-1 (Biopool), a two-stage
and indirect enzymatic assay, was used to determine plasma PAI-1
levels.1,27 In stage one, a fixed amount of t-PA
was added and allowed to react with the PAI-1 in the sample. In stage
two, the residual t-PA was measured by adding the sample to a mixture
of Glu-plasminogen, poly-D-lysine, and
chromogenic substrate at neutral pH. The PAI-1 content of
the sample was then identified as the difference between the amount of
t-PA added and the amount of t-PA found. One unit of PAI-1 activity is
defined as the amount of PAI-1 that inhibits 1 IU of human single chain
t-PA as calibrated against the international standard for t-PA lot
86/670 distributed by NIBSAC. The intra-assay and interassay
coefficients of variation were 4% and 11%, respectively.
Others
Serum triglycerides were measured with an enzymatic
colorimetric procedure (Technicon DAX 96 multichannel
analyzer, Bayer Diagnostics). Data for
triglycerides were missing in 13 twin pairs.
Height (meters) and weight (kilograms) were obtained from subjects dressed in lightweight clothes with their shoes removed. BMI was calculated as weight in kilograms/height in meters squared.
Information on medications was collected from mailed questionnaires and interview data.
Statistical Analyses
For all measures, means, SDs, and 10th, 50th, and 90th
percentiles are reported. Natural log transformations for PAI-1 and
triglycerides were used in the subsequent analyses.
Residuals from linear regression models after adjustment for age, sex,
and age-sex interactions were used in the genetic
analyses.28 Intraclass correlations and
cross-twin–cross-trait correlations are presented to compare
the differences in similarity between the four twin groups.
Multivariate genetic techniques were used to estimate
the relative importance of genetic and environmental influences unique
to PAI-1 as well as genetic and environmental influences shared by
PAI-1, triglycerides, and BMI. Genetic and environmental
correlations between PAI-1, triglycerides, and BMI were
then calculated. The statistical analyses, with the exception
of the model-fitting analyses, were carried out using the
SAS/STAT for Windows, version 6.08.
Intraclass Correlations and Cross-Twin–Cross-Trait
Correlations
The basic idea of quantitative genetic analysis is to
decompose phenotypic variance into its genetic and environmental
components29: additive effects of genes; shared
familial environmental effects; and individual-specific environmental
effects. It is assumed that the genetic variation observed for a trait
is caused by additive genetic effects, ie, the sum of several genes.
The combination of twin and adoption designs can also separate the
shared rearing environmental effects from residual-familial
environmental effects. Factors producing residual-familial
environmental effects, both for twins reared apart and reared together,
may be due to prenatal influences, postrearing contact, or similarities
in aspects of adult lifestyle such as dietary habits. Similarity within
twin pairs for each trait was assessed by intraclass correlations.
Greater intraclass correlations for MZ twin pairs than those for DZ
twin pairs for a trait indicate the importance of genetic influences
for a trait. Higher intraclass correlations for twins reared together
than those for twins reared apart indicate the influence of rearing
environmental effects. If intraclass correlations for MZ pairs are
lower than twice those for DZ pairs, the importance of
residual-familial environment is suggested.
Comparisons of cross-twin–cross-trait correlations provide information on the importance of genetic and environmental effects shared by two traits. Higher cross-twin–cross-trait correlations in MZ pairs than those in DZ pairs suggest the importance of genetic influences shared by the two traits. Greater cross-twin–cross-trait correlations in twin pairs reared together than those in twin pairs reared apart suggest the importance of rearing environmental effects shared by two traits. If cross-twin–cross-trait correlations in MZ pairs are lower than twice the cross-twin–cross-trait correlations in DZ pairs, the importance of residual-familial environmental effects shared by two traits is indicated.
Multivariate Genetic Analysis
Model-fitting approaches allow all twin groups to be
analyzed simultaneously, providing more power;
assumptions are explicit and the relative fit of nested models may be
tested. In the present model-fitting analyses,
variance-covariance matrices from four twin groups (MZA, MZT,
DZA, and DZT) were subjected to the LISREL 7 program for linear
structural equation modeling.30 The use of LISREL
in cardiovascular studies of the SATSA material has
been presented elsewhere.31,32
Variance-covariance matrices from the four groups were
analyzed simultaneously in a model with the
expectations that MZ twin pairs share 100% of their genetic effects
and DZ twin pairs share 1/2 of their segregating genes, that more
similarity in twin pairs reared together than twin pairs reared apart
is due to shared-rearing environmental effects, and that residual
similarity of twin pairs regardless of rearing status is due to
residual-familial environmental effects. The expected
covariance of shared rearing environmental factors is 1 for
twin pairs reared together and 0 for twin pairs reared apart. The
expected covariance of residual-familial environmental factors
for all twin pairs is set to 1.
To assess the relative importance of genetic and environmental
influences on PAI-1 and the genetic and environmental influences shared
by PAI-1, triglycerides, and BMI as well, Cholesky
decomposition models as described in detail by Neale and
Cardon33 were applied. These models have
previously been applied to the SATSA study.31,32
Regarding genetic factors, three latent factors
(G13, G23, and
G33) load on PAI-1, two latent factors
(G12 and G22) load on BMI,
and one factor (G11) loads on
triglycerides (the Figure
).
Shared-rearing, residual-familial, and individual-specific
environmental factors load on the four measures in a pattern similar to
the genetic factors.
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The significance of genetic and environmental effects (unique or
common) was tested by comparing the 
2 for
reduced models in which one or more parameters were fixed
to zero against the model without reduction of parameters.
If the probability value of the 2 difference
between the nested, reduced model and the full model is <.05, the
parameters dropped are considered significant. The best fit
model was judged by AIC,34 ie,
2-2 df. A constant of 50 was added
to the AIC. A model with the lowest value of this index was said to fit
the data best. The percentage of phenotypic variance for PAI-1 due to
each of the parameters was then computed from the
best-fitting model as
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The genetic correlation between PAI-1 and the other measures was also calculated as the genetic covariance between two measures divided by the square roots of the genetic variances for the two measures. Environmental correlations were calculated in a similar fashion.
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Results |
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Descriptive Results
Table 1
shows means, standard
deviations, 10th, 50th, and 90th percentiles for the measurements of
PAI-1, triglycerides, and BMI by zygosity and rearing
groups. No significant differences for plasma levels of PAI-1 and BMI
were detected across three of the twin groups (MZA, MZT, and DZA).
However, the levels of PAI-1, triglycerides, and BMI in the
DZT group were slightly lower than those in the other three groups.
Overall, the distributions of PAI-1, triglycerides, and BMI
are comparable to a general middle-aged and elderly population.
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Intraclass Correlations and Cross-Twin–Cross-Trait
Correlations
Table 2 shows the intraclass
correlations and cross-twin–cross-trait correlations for plasma PAI-1,
triglycerides, and BMI. On average, MZ twins have higher
correlations than DZ twins for plasma PAI-1, indicating the importance
of genetic influences on plasma PAI-1 levels. The intraclass
correlations for twins reared together were not higher than those for
twins reared apart, indicating that shared rearing environmental
factors were not important. Table 2 also presents the results for
cross-twin–cross-trait correlations. On average, the
cross-twin–cross-trait correlations for PAI-1 and
triglycerides, PAI-1 and BMI in MZ twins were higher than
those in DZ twins, indicating the importance of genetic contributions
to phenotypic associations between PAI-1, triglycerides,
and BMI. The cross-twin–cross-trait correlations between PAI-1 and BMI
in twin pairs reared together were, on average, higher than those in
twin pairs reared apart, indicating the importance of rearing
environmental effects shared by PAI-1 and BMI.
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Multivariate Genetic Analyses
Table 3 shows the results from
the full AEsEcEns model and nested model testing. The model-fitting
statistic for the full model was (2=90,
df=60, P=.01). When five parameter
estimates (es22, es23,
g33, es33, and
ec33) with zero values were fixed in model 1, the
model fit was improved (2=90.46,
df=65, P=.02). Further fixation of all
parameter loadings (es11,
ec22, ens22,
ens13, g23,
ec23, and ens23), which
explained <5% of the individual differences in each trait in model 2
did not result in a poorer fit of the model (difference in
2=9.41, df=7, P>.05,
when compared to model 1), indicating that these parameters
were not significant. These parameters were thus fixed to
zero in all subsequent models. Model 3 tested whether the genetic
influences shared by PAI-1, triglycerides, and BMI were
significant (g12 and g13
were fixed to zero). The fit of this model was significantly worse than
that of model 2 (difference in 2=48.69,
df=2, P<.001), suggesting that the genetic
influences shared by PAI-1, triglycerides, and BMI are
significant. Model 4 tested whether the rearing environmental effects
shared by PAI-1 and BMI were significant by fixing
es12 and es13 to zero.
Model 4 fitted the data worse than model 2 (difference in
2=7.18, df=2, P<.05),
indicating that rearing environmental effects shared by PAI-1 and BMI
are significant. Model 5 tested whether the residual-familial
environmental influences in common with PAI-1 and
triglycerides were significant (ec11
and ec13 were fixed to zero). The fit of this
model was significantly worse than that of model 2 (difference in
2=20.66, df=2, P<.01),
suggesting that the residual-familial environmental influences shared
by PAI-1 and triglycerides were significant. Using these
comparisons of models and the AIC index, we concluded that model 2 fit
the data best.
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In the present statistical models, point estimates for the genetic
and other environmental parameters were given based on the
maximum likelihood test. These kinds of point estimates are influenced
by sample size. To have a clear view of the parameters,
standard errors for the parameters were also
presented in the table 4 for
model 1 and the best fitting model (model 2). Additionally, percentages
of variances explained by different genetic and environmental
influences are also given. From the best-fitting model, the
heritability estimate for PAI-1 was 42% (42%+0%+0%), the proportion
of variance due to individual-specific environmental factors for PAI-1
was 36% (0%+0%+36%), the proportion of variance due to rearing
environmental factors for PAI-1 was 10% (10%+0%+0%), and the
proportion of variance due to residual-familial environmental factors
for PAI-1 was 12% (12%+0%+0%). All of the genetic variance for
PAI-1 was shared with the genetic variance for
triglycerides and BMI. There were no genetic influences on
PAI-1 independent of influences on the other measures. All the rearing
environmental influences on PAI-1 were shared with rearing
environmental influences on BMI (10%), and all the residual-familial
environmental influences on PAI-1 were shared with residual-familial
environmental influences for triglycerides.
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Genetic and environmental correlations between PAI-1, triglycerides, and BMI were also calculated. The genetic correlations were 1.00 between PAI-1 and triglycerides, and 0.63 between PAI-1 and BMI, indicating that the genetic influences for PAI-1 levels shared with those for triglycerides completely and with those for BMI substantially. The rearing environmental correlation between PAI-1 and BMI was 1.00, and the residual-familial environmental correlation between PAI-1 and triglycerides was 1.00, suggesting that environmental factors also contribute to the phenotypic association between PAI-1, triglycerides, and BMI.
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Discussion |
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By using quantitative genetic methods in a population-based sample of middle-aged and elderly twins reared apart and twins reared together, we found that genetic influences were important for explaining individual differences in plasma levels of PAI-1, accounting for about 42% of the total variance of plasma PAI-1 level. Individual-specific environmental factors accounted for 36% of the variation in plasma levels of PAI-1. The remaining variation in PAI-1 was explained by rearing environmental factors in common with BMI and residual-familial environmental factors in common with triglycerides. Furthermore, a substantial genetic association between PAI-1 and triglycerides and a modest genetic association between PAI-1 and BMI were found.
Heritability has been estimated for several other cardiovascular risk factors, such as blood pressure levels, blood lipids, lipoproteins, lipoprotein(a), and insulin resistance, from both family and twin studies.31,32,35–37 To our knowledge, this is the first heritability estimate reported for PAI-1. It should be remembered that the present quantitative genetic analyses were based on additive models which assume that the genetic variation observed for a trait is caused by the sum of several genes. The methods as applied here could not be used to evaluate the importance of single gene effects even if they were present.
More interestingly, multivariate genetic analyses were applied to examine whether genetic and environmental influences on PAI-1 are shared with the same influences on triglycerides and BMI. Multivariate genetic analyses have previously been applied in evaluating the associations among several of the cardiovascular risk factors.31,32,38–42 In our previous study on the genetic and environmental architecture of features of insulin resistance syndrome,32 we found that there may be considerable pleiotropy for the genes influencing the levels of insulin resistance and BMI but somewhat less genetic covariance for the levels of the other three components. Multivariate findings of this sort may provide potential insights for subsequent linkage and association studies, in that relevant candidate loci are those that influence sets of cardiovascular risk factors.43
In the present study, we found that the genetic influences unique to PAI-1 were not significant, indicating that all the genetic influences on PAI-1 are related to the genetic influences on triglycerides or BMI. In previous studies, gene polymorphisms in the PAI-1 gene were related to plasma PAI-1 levels and coronary heart disease.11–14,44 Several other studies have found significant influence of PAI-1 genotype on the association between PAI-1 levels and triglycerides.13,45 Thus, the PAI-1 genotype may be one source of genetic influences shared by PAI-1 and triglycerides. Because effects of the interactions between PAI-1 genotype and triglyceride levels on PAI-1 activity were not found in another study,14 some other genes that are responsible for the metabolism of PAI-1 and triglycerides may play more important roles. In recent studies, Bruckert and associates46,47 found that the concentration of the hepatic enzymes glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase could be mechanistic links between PAI-1 and hyperlipidemia.
Furthermore, LDL-receptor–related protein has been found to be involved in the cellular uptake of lipoprotein and plasminogen activator-inhibitor complex.48 It could be that gene mutations of these enzymes or some other hepatic enzymes may explain the genetic effects shared by PAI-1 and triglycerides. Because we found that genetic effects of importance for BMI also influenced PAI-1 levels, candidate genes for obesity might play roles in influencing PAI-1 levels.
In addition to genetic factors, some environmental factors were also found to contribute to the associations between PAI-1, triglycerides, and BMI. The effects of familial environmental factors on blood pressure, blood lipids, and some other cardiovascular risk factors have been suggested in several studies.49,50 It is likely that twins or family members share the same dietary habits and physical activity habits. A low-fat diet and weight loss were reported to be effective in reducing PAI-1 levels in addition to BMI levels in previous studies.51,52 These environmental factors may explain many of the rearing environmental influences shared with PAI-1 and BMI found in the present study. The importance of intrauterine environmental influences on blood pressure, factor VII, impaired glucose tolerance, etc, has been raised by Barker and others.53–56 If postrearing contact is not important, the contents of residual-familial environmental factors in the present study would represent prenatal environmental factors. Thus, intrauterine environment may also contribute to the individual differences in plasma levels of and the associations between PAI-1 and triglycerides to some degree.
Questions might be raised regarding the generalizability of the results from twins. Given that plasma levels of PAI-1 and most other measures fall within the range of the general population of the same age, we believe that these results can be generalized to a general population of the same age group.
In studies of aging populations, there may be selection or survival bias due to early deaths of subjects with high susceptibility to diseases. This kind of bias could underestimate the studied associations. If genetic effects on diseases or disease risk factors are present, the heritability for them could be underestimated. Therefore, caution should be made in generalizing our results to younger populations.
Another methodologic point concerns the measurement error, especially for PAI-1 as there is a considerable circadian variation. Although most of the samples were drawn in the morning under fasting conditions, some of them were not taken early in the morning due to practical problems because twins were located across Sweden and we had to visit their homes to take blood samples. These kinds of measurement errors usually overestimate individual-specific environmental effects (Ens), and underestimate other parameter estimates including the heritability estimate. If we assume that there is no difference for MZ or DZ twin pairs in attendance for blood sampling, the bias of parameter estimates due to circadian variation could be minimized.
In conclusion, genetic influences on plasma PAI-1 were found to be moderate. Furthermore, genetic effects and residual-familial environmental factors explained the phenotypic associations between PAI-1 and triglycerides. In contrast, genetic effects and rearing environmental factors contributed to the observed phenotypic associations between PAI-1 and BMI. It appears that all the genetic influences on PAI-1 are shared with genetic influences for triglycerides and BMI.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The Swedish Adoption/Twin Study of Aging (SATSA) has been supported by grants from the National Institute of Aging (AG-04563 and AG-10175), the MacArthur Foundation Research Network on Successful Aging, and the Swedish Council for Social Research. In addition, support for this study has been provided by the Swedish Medical Research Council (09533), King Gustav the V and Queen Victoria's Foundation, and the Swedish Lung and Heart Foundation.
Received March 21, 1997; accepted August 11, 1997.
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