© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Evidence That Multiple Genes Influence Baseline Concentrations and Diet Response of Lp(a) in Baboons
From the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex.
Correspondence to David L. Rainwater, PhD, Department of Genetics, Southwest Foundation for Biomedical Research, PO Box 760549, San Antonio, TX 78245-0549. E-mail david{at}darwin.sfbr.org
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Abstract—We investigated the response of lipoprotein(a) [Lp(a)] levels to dietary fat and cholesterol in 633 baboons fed a series of 3 diets: a basal diet low in cholesterol and fat, a high-fat diet, and a diet high in fat and cholesterol. Measurement of serum concentrations in samples taken while the baboons were sequentially fed the 3 diets allowed us to analyze 3 Lp(a) variables: Lp(a)Basal, Lp(a)RF (response to increased dietary fat), and Lp(a)RC (response to increased dietary cholesterol in the high-fat environment). On average, Lp(a) concentrations significantly increased 6% and 28%, respectively, when dietary fat and cholesterol were increased (P<0.001). As expected, most of the variation in Lp(a)Basal was influenced by genes (h2=0.881). However, less than half of the variation in Lp(a)RC was influenced by genes (h2=0.347, P<0.0001), whereas the increase due to dietary fat alone was not significantly heritable (h2=0.043, P=0.28). To determine whether Lp(a) phenotypic variation was due to variation in LPA, the locus encoding the apolipoprotein(a) [apo(a)] protein, we conducted linkage analyses by using LPA genotypes inferred from the apo(a) isoform phenotypes. All of the genetic variance in Lp(a)Basal concentration was linked to the LPA locus (log of the odds [LOD] score was 30.5). In contrast, linkage analyses revealed that genetic variance in Lp(a)RC was not linked to the LPA locus (LOD score was 0.036, P>0.5). To begin identifying the non-LPA genes that influence the Lp(a) response to dietary cholesterol, we tested, in bivariate quantitative genetic analyses, for correlation with low density lipoprotein cholesterol [LDLC; ie, non–high density lipoprotein cholesterol less the cholesterol contribution from Lp(a)]. LDLCBasal was weakly correlated with Lp(a)Basal (
P=0.018). However,
LDLCRC and Lp(a)RC were strongly correlated
(P=0.382), and partitioning the correlations revealed
significant genetic and environmental correlations
(G=0.587 and E=0.251, respectively). The
results suggest that increasing both dietary fat and dietary
cholesterol caused significant increases in Lp(a)
concentrations and that the response to dietary cholesterol
was mediated by a gene or suite of genes that appears to exert
pleiotropic effects on LDLC levels as well. The gene(s) influencing
Lp(a) response to dietary cholesterol is not linked to the
LPA locus.
Key Words: Lp(a) • apo(a) • baboons • genetics
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Introduction |
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The lipoprotein Lp(a) is a type of LDL particle that carries the defining apolipoprotein apo(a). Lp(a) concentrations are under strong genetic control, and high levels of Lp(a) have been associated with increased risk of cardiovascular disease in a number of studies.1 Approximately 90% of the variation in Lp(a) concentrations is associated with genetic variation at the LPA locus, which encodes the unique glycoprotein apo(a).2 3 4 Although most of the phenotypic variation in Lp(a) concentrations is due to LPA polymorphisms, there is substantial phenotypic variation within LPA genotype,4 5 suggesting significant effects of environmental factors, and perhaps other genes, on Lp(a) concentrations.
A number of studies have reported significant, albeit modest, effects on Lp(a) concentrations by various environmental factors. One such intensely studied factor has been diet. The type of dietary fat, for example, can exert significant effects on Lp(a), with trans fatty acids tending to increase levels and saturated fats tending to decrease levels.6 7 However, many studies investigating changes in the level of fat and/or cholesterol in the diet have found no appreciable effects on Lp(a) in humans and nonhuman primates.8 9 10 11 12 In contrast, we have reported significant increases of Lp(a) concentrations in baboons when levels of fat and/or cholesterol were increased in the diet.13 14 Preliminary analyses of data from 139 baboons indicated that sire group membership had a significant effect, suggesting that genes mediated the Lp(a) response to dietary fat and cholesterol.14
To address the question of genetic mediation of dietary response, we have expanded the earlier study to include data for 633 pedigreed baboons in 10 sire families to characterize the Lp(a) diet response.
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Methods |
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Animals
Baboons (Papio hamadryas) were maintained at the Southwest Foundation for Biomedical Research, which is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Experimental protocols were approved by the Institutional Animal Care and Use Committee. The pedigreed baboons (418 females and 215 males) belonged to 10 pedigrees ranging in size from 34 to 98 members. The baboons averaged 9.6 years old and 16.8 kg, and the study included yellow (P h cynocephalus) and olive (P h anubis) baboons and their hybrids.
Diet Protocol
The diet protocol has been described elsewhere.15
In brief, the baboons were fed a basal diet, low in fat (4% of
calories) and cholesterol (0.03 mg/kcal), for at least 7
weeks before collection of the basal diet blood sample. They were then
fed a diet enriched in fat (40% of calories from lard) and
cholesterol (1.7 mg/kcal; HFHC diet) for 7 weeks before
collection of the HFHC diet blood sample. After a 7-week washout period
on the basal diet, the baboons were then fed a diet enriched in fat
only (40% of calories from lard, 0.03 mg cholesterol/kcal;
HFLC diet) for 7 weeks before collection of the HFLC diet blood sample.
For each blood sample, baboons were fasted overnight and
immobilized with ketamine, and blood was drawn from
the femoral vein. At the time of the first sample (basal diet), the
weight (kg) of each animal was recorded. Serum was prepared by
low-speed centrifugation and stored at -80°C in
single-use aliquots as described,16 protected from
oxidation and desiccation.
Measurement of Lp(a) and LDL Cholesterol Concentrations
Serum Lp(a) concentrations were measured using a commercial kit
[Apo-Tek Lp(a), Sigma Diagnostics], which is specific for
Lp(a) particles by virtue of requiring sequential binding by antibodies
directed against both apo(a) and apoB.17 Samples were
assayed as suggested by the supplier, and all 3 diet samples from each
baboon were run together on the same plate. Control products
supplied with the kit gave coefficient of variation estimates of 8.3%
at 7.7 mg/dL (n=50) and 6.4% at 25.7 mg/dL (n=36). Assay repeatability
for baboon samples was 98.0% based on 50 replicated samples. To
further verify reliability of the assay for baboon Lp(a), we compared
Lp(a) values for the same samples14 that had been measured
with our baboon-specific assay.17 We found a high degree
of correlation for the 2 assays
(r2=0.91, n=410; data not shown).
Cholesterol concentrations were measured enzymatically18 19 with reagents supplied by Boehringer Mannheim Diagnostics and a Ciba-Corning Express Plus clinical chemistry analyzer. Cholesterol in HDL was determined in the supernatant after precipitation of apoB-containing lipoproteins with heparin-Mn2+.20 Average coefficients of variation for control products in these assays were 2.2% and 4.6% for total and HDL cholesterol, respectively. Cholesterol concentration in ß-lipoproteins was calculated as the difference between total serum and HDL cholesterol, and this value reflects contributions primarily from LDLs, with relatively minor contributions from VLDL and IDL and variable contributions from Lp(a). Although it is possible that there is some variation in lipid amount per Lp(a) particle for different diets, the Lp(a) cholesterol concentration was estimated as 30% of Lp(a) mass.21 This value was subtracted from ß-lipoprotein cholesterol to estimate the non-Lp(a)/non-HDL cholesterol concentration (termed LDLC in this report) in each sample.
Three concentration variables were calculated from assays of the 3 diet samples from each baboon: Lp(a)Basal (the basal diet values) and 2 variables representing response to dietary fat [Lp(a)RF, calculated as Lp(a)HFLC-Lp(a)Basal] and response to dietary cholesterol [Lp(a)RC, calculated as Lp(a)HFHC-Lp(a)HFLC]. These same 3 variables were also calculated for LDLC.
Determination of LPA Genotypes
LPA genotypes were inferred on the basis of
the apo(a) size polymorphism. Serum samples were treated with SDS
under reducing conditions, and apo(a) isoform phenotypes
were resolved by electrophoresis in acrylamide gradient
gels and detected using a previously described system that identifies
12 isoform sizes in baboons.13 Transmission of
parental isoforms to offspring was verified by running samples from
family members in adjacent lanes. Thus, isoform phenotypes
marked, within families, alleles that were identical by descent.
Single-banded samples can result from 1 of 2 conditions: homozygous for
size or heterozygous-null. The family analyses allowed us to
differentiate most (
86%) of the single-band cases; the
genotype field was blanked for the animals we could not
differentiate before linkage analyses were performed.
Statistical Genetic Analyses
We used univariate quantitative genetic
analyses22 to assess heritability and covariate
effects on serum Lp(a) concentrations and Lp(a) response variables.
Covariate effects (including sex, sex-specific age, and weight terms)
were simultaneously estimated with the heritabilities. We
used bivariate quantitative genetic analyses on LDLC and Lp(a)
data to simultaneously calculate the means, SDs, residual
heritabilities, and covariate effects for each trait, as well as
genetic (G) and environmental
(E) correlations between
traits.23 Nonzero genetic correlations between traits
imply that the same gene or genes influence both traits. Total
phenotypic correlations (P) were calculated as
P=
h12
· h22 ·
G+(1-h12)
· (1-h22) ·
E, where
h12 and
h22 represent
heritabilities for traits 1 and 2, respectively. Probability values
were estimated, using likelihood-ratio tests, by comparing the
likelihood of a model allowing for the parameter with the
likelihood of a model in which the parameter was fixed at
zero.
To test whether the LPA locus was linked to quantitative
trait loci (QTLs) for the different Lp(a) phenotypes, we used
variance component methodologies as implemented in the computer program
SOLAR.24 25 Variance component
methodologies are a strategy to estimate the proportion of the total
phenotypic variance that is attributable to the region around a
specific genetic locus, ie, a test for linkage.26 In
SOLAR, the expected genetic covariance between
relatives is modeled as a function of the identity-by-descent
relationships at the marker locus. By using maximum likelihood methods,
the total phenotypic variance can be partitioned into components due to
covariate effects, LPA locus effects, and residual additive
genetic effects (heritability). The likelihood-ratio statistic, which
is asymptotically distributed as a 
2, was used
to test whether the variance attributable to allele sharing among
relatives at the LPA locus was significantly greater than
zero.
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Results |
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Significant Effects of Dietary Fat and Cholesterol on Baboon Lp(a)
The 633 pedigreed baboons that underwent the diet protocol averaged 9.4, 10.0, and 12.8 mg Lp(a)/dL when fed the basal, HFLC, and HFHC diets, respectively. On average, Lp(a) concentrations increased by 6% and 28%, respectively, in response to increasing dietary fat [ie, Lp(a)RF] and dietary cholesterol [ie, Lp(a)RC], and the increases were significant (P<0.001, paired t test). The Figure
presents frequency histograms for the
effect of dietary fat (left) and dietary cholesterol
(right) on serum Lp(a) concentrations.
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Genetic Effects on Lp(a) and Lp(a) Response to Dietary
Cholesterol
We used univariate genetic analyses to
determine whether genes influence Lp(a) concentrations and their
responses to dietary fat and cholesterol. Table 1 gives trait means, covariate effects,
and heritabilities (h2) for serum
Lp(a) concentrations in the basal diet sample
[Lp(a)Basal] and the cholesterol
response variable Lp(a)RC. As expected,
heritability for serum Lp(a) concentrations on the basal diet was very
high (h2=0.881) and was even higher
for the other diets
(h2HFLC=0.948 and
h2HFHC=0.938, data
not shown). The heritability of Lp(a)RC also was
significant (P<0.0001), but moderate
(h2=0.347). However, there was no
evidence for genetic effects on Lp(a)RF
(h2=0.043±0.049, P=0.28;
data not shown).
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Tests for Linkage of Lp(a) Concentrations to
LPA
Because LPA, the locus encoding the apo(a) protein, is
known to have a strong effect on Lp(a) concentrations, we conducted
variance component linkage analyses (after assuming that
recombination, 
, was zero) between LPA and QTLs for the
heritable traits Lp(a)Basal and
Lp(a)RC. LPA genotypes,
inferred from serum apo(a) phenotypes, were available for 601
pedigreed baboons. Table 2 gives the
results of the linkage analyses. As expected for the basal
diet, all the genetic variance in Lp(a) levels was linked to the
LPA locus with a log10 of the odds in
favor of linkage (LOD) score of 30.5. However, allele sharing at
the LPA locus among relatives did not account for a
significant proportion of the variance in cholesterol
response (LOD score was 0.036, P>0.05). Therefore, there
was no evidence for linkage of a QTL for Lp(a) response to dietary
cholesterol to the LPA locus.
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Lp(a) Variation Is Genetically Correlated With LDLC
Variation
Because it is a variant LDL particle, a reasonable mechanism for
the non-LPA–related variation in Lp(a) concentrations would
be general metabolic effects on ß-lipoproteins. To test
this hypothesis, we calculated the concentrations of non-HDL
cholesterol not associated with Lp(a) (ie, LDLC) and tested
for correlation with Lp(a) concentrations. Table 3 presents the results of bivariate
genetic analyses for 2 pairs of traits, Lp(a) and LDL
concentrations for basal diet and for cholesterol response.
Bivariate analyses of fat response are not included in the
table because this trait had very low heritabilities for both Lp(a) and
LDLC. For the basal diet traits, the overall phenotypic correlation was
low (P=0.108), but significant
(P=0.013) when compared with a model in which neither
genetic nor environmental correlation was estimated. Subsequent
analyses indicated that most of this correlation was
attributable to the environmental component (ie,
E=0.332± 0.120 when
G was fixed at zero). In contrast, for the
dietary cholesterol response variables, the phenotypic
correlation was moderate (P=0.382) and, when
partitioned, both the genetic and environmental correlations were
significant. In fact, about one third of the shared variation in the 2
traits was influenced by a common suite of genes (ie,
G2=0.34).
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Discussion |
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In this study, we investigated the effects of increasing dietary fat and cholesterol on Lp(a) levels in baboons, which have been demonstrated to be excellent models for human Lp(a).13 21 27 28 29 We found that dietary fat and cholesterol significantly increased Lp(a) concentrations. This result confirms our earlier work in baboons13 14 but appears to contradict results from studies in humans that suggest either a reduction in Lp(a) with increased dietary fat30 or a lack of diet response.8 11 12 Although it is possible that Lp(a) in baboons responds to diet differently than it does in humans, it is more likely that we have detected these effects because of our ability to control dietary intake and to feed diets with large contrasts in level of fat and cholesterol.
It is important to recognize 2 methodological limitations that could
affect our results. First, the Lp(a) assay is not optimized for baboon
Lp(a). Although we found a high repeatability (98.0%) and a strong
correlation with values derived from a baboon-specific assay
(r2=0.91), it is possible that the
assay values for baboon Lp(a) are biased. Despite the potential for
affecting the actual Lp(a) values reported herein, bias will not affect
the genetic results and their interpretation so long as there is a
strong correlation with true values. Second, several studies have
reported Lp(a) binding to or associated with
triglyceride-rich lipoproteins
(TRLs)31 32 33 and LDLs34 in humans. Given
that the Lp(a) assay measures apoB levels, a consequence of such
interactions (should they occur in the assay and be diet specific)
might be to give spuriously high Lp(a) readings for some diet samples.
Although we cannot rule out this possibility, we have not observed, in
density gradient analyses,13 17 21 apo(a) proteins
in density fractions more buoyant than Lp(a). Furthermore, baboons tend
to have relatively low plasma triglyceride concentrations
(52 mg/dL on the basal diet and 37 mg/dL on the HFHC
diet35 and, consequently, low levels of TRLs.
The main thrust of our study was to determine whether dietary effects
on Lp(a) were mediated via genes as was suggested by our preliminary
study.14 Consistent with observations in studies
of humans,36 37 we found that 90% of the total
phenotypic variation in baboon Lp(a) was due to genes. However, we
found that the significant increase of Lp(a) levels in response to
increased level of dietary fat did not have a significant genetic
component. This result contrasts with that of Cantor et
al,30 who found that human Lp(a) levels significantly
decreased and that this decrease was highly heritable (maximum
h20.58). The authors also found no
significant evidence for linkage to a marker near the LPA
locus (P<0.07), suggesting that other, non-LPA
genes may mediate the response to dietary fat. In contrast to the lack
of genetic control of dietary responsiveness to fat in baboons, about
one third of the response to dietary cholesterol in the
high-fat environment was influenced by genes
(h2=0.347± 0.079,
P<0.0001). We are not aware of any previous study that has
assessed heritability of Lp(a) response to dietary
cholesterol.
After determining that basal Lp(a) and dietary cholesterol
responses were moderately to strongly influenced by genes, we tried to
identify the gene(s) by using linkage analysis. A number of
studies2 3 4 have reported that 90% of the phenotypic
variation in human Lp(a) is due to allelic variation at LPA,
the locus encoding the apo(a) protein. Similarly, we found that baboon
serum Lp(a) concentration in the 3 diet samples was strongly linked to
the LPA locus in this study as well (Table 2
). The
LOD score was 30.5 for basal Lp(a) levels, and LOD scores were even
higher for Lp(a) in the other diet samples [36.1 for
Lp(a)HFLC and 37.3 for
Lp(a)HFHC; data not shown]. We detected no
residual additive genetic variance in basal Lp(a) after accounting for
the LPA locus.
However, the Lp(a) cholesterol response variable was
not significantly linked to the LPA locus (Table 2),
suggesting that an additional gene(s) influences Lp(a) response to
dietary cholesterol. Although most studies have identified
only the LPA locus as exerting a significant effect on Lp(a)
concentrations, a few studies do suggest the possibility of additional
genes. For example, in siblings concordant for LPA
genotype but discordant for heterozygous familial
hypercholesterolemia, Lp(a) concentrations were
significantly elevated in the familial
hypercholesterolemic siblings,38
clearly demonstrating a pleiotropic effect of the LDL receptor locus on
Lp(a) levels in persons with the rare disorder familial
hypercholesterolemia. In addition, it is likely
that LPA is not 1 of the gene(s) influencing dietary fat
response in humans.30
Because Lp(a) is a type of LDL, we hypothesized that genes influencing LDL concentrations might also affect Lp(a) concentrations. Although there was no genetic correlation of serum concentrations of LDL and Lp(a) on the basal diet, there was a highly significant genetic correlation for their responses to dietary cholesterol, indicating the same gene(s) influences both cholesterol response variables. This finding is likely to be relevant to humans, since several studies4 39 40 41 have reported significant phenotypic correlation of Lp(a) and LDLC concentrations, and the present data suggest that genes mediate at least a portion of the correlation. We hypothesize that a suite of genes influences the metabolism of ß-lipoproteins, thereby exerting a pleiotropic effect on Lp(a) concentrations as well. The finding of Lingenhel et al38 suggests that the LDL receptor gene may be 1 member of that suite, and further studies should reveal additional genes.
Previously, we found evidence for an unidentified major gene that influences most of the genetic variation in the LDLCRC trait in baboons.15 Because of the strong genetic correlation of LDLCRC and Lp(a)RC, we hypothesize that the major gene for LDLCRC is the principal non-LPA locus that also influences Lp(a) concentrations in baboons. Testing this hypothesis and identification of the non-LPA gene(s) that affects Lp(a) should be facilitated on completion of the baboon genome map.42
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Acknowledgments |
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This work was supported by grant HL28972 from the National Institutes of Health (J.L.V.). The authors are grateful to Mari Hui, Jennifer Schneider, Susan Slifer, and Jane VandeBerg for technical assistance.
Received January 27, 1999; accepted April 19, 1999.
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