© 1995 American Heart Association, Inc.
Articles |
No Association Between Plasma Lipoprotein(a) Concentrations and the Presence or Absence of Coronary Atherosclerosis in African-Americans
From the Department of Cardiology, the Cleveland Clinic Foundation, Cleveland, Ohio (D.J.M.), the Departments of Internal Medicine and Molecular Genetics, University of Texas Southwestern Medical Center, and the Center for Demographics and Population Genetics, University of Texas Health Science Center (E.B.), Houston, Tex.
Correspondence to Dr Helen H. Hobbs, Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9046.
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Abstract Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with coronary atherosclerosis in Caucasians. Although African-Americans have a higher median plasma Lp(a) concentration than Caucasians, they do not have a greater incidence of coronary atherosclerosis. This study was performed to determine whether the plasma concentration of Lp(a) is associated with coronary atherosclerosis in African-Americans. The fasting plasma concentrations of Lp(a) and lipoproteins were measured in 140 African-American subjects (62 men, 78 women, aged 31 to 80 years) 18±16 months (mean±SD) after they underwent coronary angiography: 72 had angiographically normal coronary arteries and 68 had >70% luminal diameter narrowing of one or more major epicardial coronary arteries. The groups were similar in age, sex, and other risk factors for atherosclerosis. The subjects with coronary artery disease had higher plasma concentrations of total cholesterol, triglycerides, and VLDL and LDL cholesterol (P=.04) and lower concentrations of HDL cholesterol (P=.0001) than subjects without coronary artery disease, but there was no significant difference in the plasma concentration of Lp(a). The distribution of apolipoprotein(a) alleles by size was also not significantly different between the two groups. These results suggest that the plasma concentration of Lp(a) is not an independent risk factor for coronary artery disease in African-Americans.
Key Words: lipoprotein(a) • African-Americans • plasminogen
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Introduction |
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Lipoprotein(a) [Lp(a)] is a cholesterol ester–rich lipoprotein composed of an LDL particle and a large glycoprotein, apolipoprotein(a) [apo(a)].1 2 Apo(a) is highly variable in size because of length polymorphism in the apo(a) gene.1 3 Apo(a) alleles differ in the number of a tandemly repeated sequence that encodes a protein motif resembling the kringle 4 of plasminogen. Plasma Lp(a) concentrations are largely determined by sequence differences at, or closely linked to, the apo(a) locus4 and tend to be inversely related to the number of kringle 4–encoding sequences in the apo(a) gene.1 3
In a given individual, the plasma concentration of Lp(a) is remarkably constant and relatively uninfluenced by age and dietary intake.5 In Caucasians and Orientals the population distribution of plasma Lp(a) levels is highly skewed, so that most individuals have low circulating levels of plasma Lp(a).1 5 6 7 In these populations, high plasma concentrations of Lp(a) (more than 20 to 30 mg/dL) tend to be associated with an increase in the prevalence and severity of coronary artery disease (CAD).7 8 9 10 In contrast, the population distribution of plasma Lp(a) levels in Africans and African-Americans is more symmetric; these populations therefore have a mean plasma concentration of Lp(a) two times higher than that in either Caucasians or Orientals.1 11 12 13 14 15 16 17 Despite having significantly higher plasma Lp(a) concentrations, African-Americans have a similar or lower prevalence of ischemic heart disease than Caucasians.18 19 20 21 22
Only one study has examined the relationship between plasma Lp(a) concentrations and CAD in African-Americans with angiographically defined coronary arteries.23 In that study, the plasma Lp(a) levels of 32 African-Americans without CAD were compared with those in 79 subjects with CAD. The plasma concentrations of Lp(a) tended to be higher in the subjects with CAD, but the difference was not statistically significant.23 To investigate further whether high plasma concentrations of Lp(a) are associated with atherosclerotic CAD in African-Americans, plasma Lp(a) levels and size distribution of apo(a) alleles were compared in African-Americans with angiographically normal coronary arteries or significant CAD.
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Methods |
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Patient Population
A total of 364 African-American patients underwent coronary angiography at Parkland Memorial Hospital in Dallas, Tex, between January 1988 and December 1991. All cineangiograms were reviewed by two experienced angiographers and categorized as showing (1) normal coronary arteries (<10% diameter stenosis), (2) minor CAD (
10% to
70% diameter stenosis), or (3) significant coronary
atherosclerosis (>70% luminal diameter narrowing of
one or more major epicardial coronary arteries). All patients
with 10% to 70% diameter stenosis of a single epicardial
vessel were then excluded, as were those with a confounding chronic
illness such as end-stage renal disease, steroid-treated immunologic
disorder, or poorly controlled diabetes mellitus (n=49). Therefore, 315
subjects (237 with and 78 without CAD) were eligible for enrollment.
Efforts were made to contact all 315 subjects. Twenty-six could not be
located (23 with CAD and 3 without CAD) and 7 had died (all with CAD).
Of the remaining 282 subjects, the 140 who were scheduled for routine
outpatient follow-up between December 1991 and February 1992 were
contacted before the clinic visit, and all agreed to participate in the
study. Of these 140 (62 men and 78 women, aged 31 to 80 years), 72 had
angiographically normal coronary arteries (Group I) and 68 had
CAD (Group II). The study protocol was approved by the Human Subjects
Review Committee of The University of Texas Southwestern Medical
Center, and all subjects gave written informed consent.
Variables Assessed
The medical record of each patient was reviewed, and each
patient was interviewed to determine the presence of risk factors for
atherosclerotic cardiovascular disease. All medications
were noted. Fasting venous blood samples were obtained between 8:00
AM and 10:00 AM in tubes containing EDTA or
buffered citrate. The blood was maintained at 4°C, and the plasma was
separated by centrifugation (2000g for 20
minutes) within 1 hour. The time interval from
catheterization to procurement of blood was 18±16
months (mean±SD). No blood was sampled from subjects within 6 months
of having unstable angina, myocardial infarction, or bypass
surgery.
Plasma lipoprotein cholesterol concentrations were measured according to the procedures of the Lipid Research Clinics.24 Total plasma cholesterol and triglycerides were measured with enzymatic assay kits (Boehringer Mannheim Biochemicals and Sigma Chemical Co). Fibrinogen was measured by a standardized polymerization method (Dade Diagnostica). The plasminogen assay was performed with samples incubated in an excess of streptokinase, and the plasminlike activity was measured in the presence of a chromogenic substrate (Kabi Diagnostica, Helena Laboratories). The plasma concentrations of Lp(a) were measured by use of a sandwich enzyme-linked immunosorbent assay (GeneScreen Laboratories), according to the method of Menzel et al25 and as previously described.3 In brief, the capture antibody was an affinity-purified polyclonal rabbit anti-human apo(a) antibody and the detection antibody was a mouse monoclonal anti-apo(a)–specific antibody (IgG-1A2). The epitope for this antibody resides within the kringle 4 repeat (written communication, Gerd Utermann, MD, 1994). The standard used in the assay was supplied by Immuno AG and had a concentration of 52.4 mg/dL. Two assays were performed in duplicate on plasma samples from each subject, and the average of the concentrations was used for these analyses. The rank correlation coefficient between the two Lp(a) measurements was 0.96.
Immunoblot Analysis of Apo(a) Isoforms
Apo(a) isoform analysis was performed by use of a
modification of the immunoblotting method of Kamboh et
al26 as previously described.24 The isoforms
were designated according to the total number of kringle 4 repeats
contained within their sequence [apo(a)K-12 to apo(a)K-51], as
determined by relative comigration with previously characterized
standards.27 The kringle 4–encoding region of the apo(a)
gene was analyzed directly by pulsed-field gel analysis
in the subset of individuals in whom no apo(a) isoform (one subject in
Group I and one in Group II) or only a single apo(a) isoform (18
subjects in Group I and 25 in Group II) was visible by
immunoblotting.
Pulsed-Field Gel Electrophoresis and Genomic Blotting
High–molecular weight genomic DNA was isolated from mononuclear
cells obtained from 16 mL of blood3 and subjected to
digestion with HpaI. The DNA fragments were size
fractionated using pulsed-field gel electrophoresis, and genomic
blotting was performed with an apo(a)-specific probe as previously
described.24 The apo(a) alleles were sized according
to their relative migration to known standards and designated according
to the total number of kringle 4–encoding sequences in the apo(a)
gene.27 In three subjects without CAD, no high–molecular
weight genomic DNA was available for performance of the
pulsed-field gel analysis, so their data are not included in
the apo(a) allele frequency data.
Statistical Methodology
All data are reported as the median and mean±SD. Subjects with
angiographically normal coronary arteries (Group I) were
compared with those with CAD (Group II) by use of a Mann-Whitney
rank-sum test for continuous variables28 and a
2 test for categorical variables. Because of
the large number of apo(a) alleles, traditional
2 tests of independence were inappropriate for
examination of the relationship between CAD and apo(a) alleles.
Comparison of apo(a) allele frequencies between groups was carried
out using a Monte Carlo approximation to Fisher's exact
test.29 The power of the Mann-Whitney rank-sum test was
confirmed (calculated to be >85%) by use of the formulas provided by
Noether.30 Stepwise logistic regression31 was
performed to assess the ability to use a subject's plasma Lp(a)
concentrations to determine the probability of his or her having CAD
while other predictor variables were simultaneously
considered. For all analyses, a value of P<.05
was considered significant. Following the suggestion of
Rothman,32 we made no adjustments for multiple
comparisons.
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Results |
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The African-American subjects in Groups I and II were similar in age, sex, estrogen status for women, and the presence of other risk factors for atherosclerotic cardiovascular disease (Table 1
). There was a high frequency of cardiac risk
factors in both groups because people with multiple risk factors in
this population are much more likely to obtain a cardiac catherization
than those without such factors. More subjects with CAD were taking
ß-blockers, aspirin, or hypolipidemic agents (Table 1). Among those
with CAD, six were receiving lovastatin, one was receiving
cholestyramine, and one was receiving gemfibrozil, whereas only one
subject in the group with normal coronary arteries was
receiving lovastatin. Bile acid resins,
3-hydroxy-3-methylglutaryl coenzyme A–reductase
inhibitors, and gemfibrozil in the given doses do not
significantly influence the plasma concentration of
Lp(a).33 34
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The two groups had similar concentrations of fibrinogen and
plasminogen but differed significantly with respect to
plasma lipoprotein concentrations (Table 2). Despite
there being a higher percentage of subjects taking lipid-lowering
agents in Group II, these patients had significantly higher plasma
concentrations of total cholesterol,
triglycerides, VLDL cholesterol, and LDL
cholesterol as well as lower plasma levels of HDL
cholesterol. In contrast, there was no significant
difference in the plasma concentrations of Lp(a) in the two groups: the
median plasma Lp(a) concentrations were identical (42 mg/dL), and the
mean plasma concentration of Lp(a) was 54±47 mg/dL for Group I
patients and 52±38 mg/dL for Group II patients (P=.90).
When data from only those not taking lipid-lowering medications were
analyzed, plasma Lp(a) concentrations remained similar for the
two groups (Table 3).
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In subjects with and without angiographically significant CAD, the
distribution of plasma Lp(a) levels was similar (Fig 1).
The frequency of low and high plasma Lp(a) levels (defined as levels
below or above the sample median, respectively) was not significantly
different in the two groups (2=0.03, 1
df; P=.87); 35 Group I subjects (49%) and 34
Group II subjects (50%) had Lp(a) levels that were higher than the
mean. With stepwise logistic regression analyses, use of plasma
Lp(a) concentrations did not improve the ability to predict the
probability of a subject's having CAD (data not shown). The
significant predictors of CAD in this sample of African-Americans were
age, total cholesterol, and HDL cholesterol.
When these variables were considered, plasma Lp(a) concentrations
did not contribute to the prediction of a patient's having CAD
(P=.72).
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Previous studies have suggested that Lp(a) may interact with other
factors, such as plasma LDL cholesterol, to increase the
risk of CAD.13 35 To investigate further the apparent lack
of association between plasma Lp(a) concentration and the presence of
CAD in African-Americans, the distribution of Lp(a) was compared in
subgroups of individuals with and without angiographically significant
CAD (Table 3
). There was no difference in plasma Lp(a) levels when men
and women were analyzed separately or in subjects with elevated
plasma LDL cholesterol, triglycerides,
plasminogen, or fibrinogen or reduced plasma concentrations
of HDL cholesterol. In addition, plasma Lp(a) levels were
similar in smokers and nonsmokers, subjects with and without
hypertension or diabetes (data not shown), and those receiving and not
receiving hypolipidemic medications. Postmenopausal women had notably
higher plasma levels of Lp(a) than premenopausal women regardless of
CAD status (71 mg/dL and 43 mg/dL, respectively).
To determine whether there were differences in the size distribution of
apo(a) alleles in the two groups, the apo(a) genotypes were
determined by apo(a) isoform immunoblotting and by pulsed-field gel
electrophoresis and genomic blotting of the apo(a) gene. Previous
studies have demonstrated a direct relationship between apo(a) gene
length and apo(a) isoform size,3 so in subjects in whom
both apo(a) isoforms were visible the apo(a) alleles were
determined by immunoblotting alone. The kringle 4–encoding region of
the apo(a) gene was analyzed directly by pulsed-field gel
analysis in samples in which no apo(a) isoform or only a single
apo(a) isoform was visible by immunoblotting. The length distribution
of apo(a) alleles is shown in Fig 2. The number of
kringle 4 repeats in the apo(a) alleles ranged from 12 to 38 in
those with CAD (Fig 2A) and from 12 to 43 in those without CAD (Fig 2B). As expected, based on the sample size and the large number of
alleles, there were some differences in the relative frequencies of
selected alleles. However, there was no significant difference in
the overall apo(a) allele size distributions between the two groups
(P=.78).
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Discussion |
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In this study, plasma Lp(a) concentrations and the distributions of apo(a) allele sizes were compared in African-Americans with and without angiographically significant CAD. There was no significant difference in the levels of plasma Lp(a) or the distribution of apo(a) isoform sizes between the two groups.
Two previously published studies have examined the relationship between plasma Lp(a) levels and CAD in African-Americans, and their results are consistent with our findings. In the Bogalusa Heart Study, plasma Lp(a) concentrations were measured in Caucasian and African-American children with and without a parental history of myocardial infarction.36 37 Caucasian children with a parental history of myocardial infarction had a significantly higher plasma level of Lp(a) than those without a parental history of ischemic cardiac events.37 In contrast, in the African-American group, there was no significant difference between the plasma concentrations of Lp(a) of children with and without a parental history of myocardial infarction. A cross-sectional study of the plasma Lp(a) concentrations in African-Americans from a northern US urban population found no significant difference in plasma Lp(a) levels in those with and without angiographically defined CAD.23
In this study, there were more postmenopausal women in the group
without CAD (n=33) than in the group with CAD (n=20), but the numbers
of estrogen-positive women (ie, premenopausal women and postmenopausal
women who were taking estrogen) and estrogen-negative women (ie,
postmenopausal women not taking estrogen) were not significantly
different (Table 1). In Caucasians, postmenopausal women have an
10% to 50% increase in plasma Lp(a) levels compared with
premenopausal women.38 39 The postmenopausal women in this
study who were not on estrogen supplementation had significantly higher
median plasma Lp(a) levels than their premenopausal counterparts (Table 3). In Caucasians, estrogen therapy is associated with a decrease in
plasma Lp(a) levels in both women and men.40 41 42 The number
of postmenopausal women receiving estrogen replacement in this study is
too small for the effect of estrogen on plasma Lp(a) levels to be
evaluated. No study to date has examined the effect of estrogen
replacement on plasma Lp(a) levels in African-Americans.
Our study has certain limitations. First, it is a retrospective study of African-Americans referred for coronary angiography over a 4-year period. Of the 282 subjects eligible for study, blood was collected from an unselected sample of 140 who had a follow-up visit planned during the 3-month study enrollment. The groups were well matched for age, sex, and coronary risk factors. We cannot exclude the possibility that our results would have been different if all 282 subjects had been studied. Second, because many of our patients had risk factors for atherosclerotic cardiovascular disease, we cannot assess the association of plasma Lp(a) with CAD in African-Americans without other risk factors. Finally, we excluded patients with mild to moderate (10% to 70%) coronary arterial stenoses. Thus, we cannot comment on the possible, although unlikely, association of Lp(a) with intermediate CAD.
However, our study has certain strengths. It is the largest published study assessing the association of plasma Lp(a) concentrations with angiographically proven CAD in African-Americans, and it is the only study to assess the distribution of apo(a) allele sizes in African-Americans with and without CAD. Moreover, the patient cohorts were angiographically distinct in that only those with a coronary lumen diameter stenosis of less than 10% or more than 70% were studied.
The lack of association between plasma concentrations of Lp(a) and CAD may reflect unidentified (genetic or environmental) differences between the Caucasian and African-American populations. African-Americans may be protected from the atherogenic effect of high plasma concentrations of Lp(a) by counterbalancing factors. For example, compared with Caucasians, African-Americans (especially men) have higher plasma concentrations of HDL cholesterol and lower concentrations of LDL cholesterol,43 44 which may attenuate the atherosclerotic potential of Lp(a). In addition, studies have suggested that African-Americans have a greater sensitivity to tissue plasminogen activation than do Caucasians.45 This is of particular interest in light of numerous in vitro studies that have demonstrated that high concentrations of Lp(a) can interfere with plasmin generation.2
The apo(a) glycoprotein is highly polymorphic in length; a total of 34 differently sized apo(a) isoforms can be distinguished by use of agarose gel electrophoresis and immunoblotting.27 46 Differently sized apo(a) alleles may result in variability in the presence or number of atherogenic-promoting sequences. Some but not all studies that have compared the frequency distribution of apo(a) isoforms in Caucasians and Orientals with and without CAD have found that the smaller apo(a) isoforms are more frequent in subjects with CAD.17 46 47 48 Importantly, in our study of African-Americans, we found no significant difference in the distribution of apo(a) alleles by size in those with or without CAD. However, our analysis does not exclude the possibility that the apo(a) alleles in the African-American population (irrespective of their size) may differ in sequence from those in other populations. Apo(a) sequence(s) that are responsible for mediating the atherogenic or thrombogenic effects of Lp(a) may not be as prevalent in the African-American population.
The atherogenic potential of Lp(a) may differ between African-Americans and other populations. In Caucasians and Orientals, most cross-sectional studies and some49 50 51 but not all52 53 54 prospective studies have found that high plasma levels of Lp(a) are associated with CAD (for review, see Reference 5555 ). The reason for the lack of an association between elevated plasma Lp(a) levels and cardiac events in three prospective studies52 53 54 is not known, but it may be due to methodological problems associated with measuring plasma Lp(a) levels after prolonged storage. Alternatively, these discrepant results, together with our finding of no association between plasma Lp(a) levels and the presence or absence of CAD in African-Americans, may suggest that elevated plasma Lp(a) levels are not uniformly associated with an increased cardiac risk.
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Acknowledgments |
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This work was supported in part by grants from the Perot Family Foundation and Bristol-Myers Squibb and by National Institutes of Health grants HL-47619, HL-20948, and HL-40613. Dr Jokinen is a recipient of an award from the Paulo and Ella och George Ehnroot Foundations. Dr Miserez is supported by the Swiss Foundation for Medical-Biological Grants. Dr Boerwinkle is the recipient of a Research Career Development Award from the National Institutes of Health. Dr Boerwinkle and Dr Hobbs are Established Investigators of the American Heart Association. We acknowledge the assistance of Scott Grundy, MD, PhD, for performing the lipid assays and Joy Ashcraft, Anne Kim, and Susanne Weant for performing the assays of plasminogen and fibrinogen.
Received February 12, 1995; accepted March 20, 1995.
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