© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
High Levels of Lp(a) With a Small Apo(a) Isoform Are Associated With Coronary Artery Disease in African American and White Men
From the Department of Medicine (F.P., C.H.T., J.R., L.B.), Columbia University, New York, NY; Bassett Research Institute (T.A.P., H.F.C.W., M.M., H.F.M., E.F.P., R.G.R.), Cooperstown, NY; University of Rochester (T.A.P.), Rochester, NY; and Harlem Hospital (C.K.F.), New York, NY.
Correspondence to Lars Berglund, MD, Department of Medicine, Room P&S 9-510, Columbia University, 630 West 168th St, New York, NY 10032. E-mail LFB9{at}columbia.edu
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Abstract—Elevated levels of lipoprotein(a) [Lp(a)] and the presence of small isoforms of apolipoprotein(a) [apo(a)] have been associated with coronary artery disease (CAD) in whites but not in African Americans. Because of marked race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes, we tested the hypothesis that apo(a) isoform size determines the association between Lp(a) and CAD. We related Lp(a) levels, apo(a) isoforms, and the levels of Lp(a) associated with different apo(a) isoforms to the presence of CAD (
50% stenosis) in 576 white and African American men and
women. Only in white men were Lp(a) levels significantly higher among
patients with CAD than in those without CAD (28.4 versus 16.5 mg/dL,
respectively; P=0.004), and only in this group was the
presence of small apo(a) isoforms (<22 kringle 4 repeats) associated
with CAD (P=0.043). Elevated Lp(a) levels (30 mg/dL)
were found in 26% of whites and 68% of African Americans, and of
those, 80% of whites but only 26% of African Americans had a small
apo(a) isoform. Elevated Lp(a) levels with small apo(a) isoforms were
significantly associated with CAD (P<0.01) in African
American and white men but not in women. This association remained
significant after adjusting for age, diabetes mellitus, smoking,
hypertension, HDL cholesterol, LDL cholesterol,
and triglycerides. We conclude that elevated levels of
Lp(a) with small apo(a) isoforms independently predict risk for CAD in
African American and white men. Our study, by determining the
predictive power of Lp(a) levels combined with apo(a) isoform size,
provides an explanation for the apparent lack of association of either
measure alone with CAD in African Americans. Furthermore, our results
suggest that small apo(a) size confers atherogenicity to
Lp(a).
Key Words: lipoprotein(a) • coronary artery disease • African Americans • angiography • genetic variation
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Introduction |
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Lipoprotein(a) [Lp(a)] has been identified as a risk factor for cardiovascular disease.1 2 3 In numerous, but not all, prospective studies, mainly in white populations, elevations of plasma Lp(a) levels, usually defined as
30
mg/dL, were significantly correlated with coronary artery
disease
(CAD).4 5 6 7 8 9 10 11 12 13
Curiously, although mean Lp(a) levels are twice as high in African
Americans compared with whites, studies to date have failed to
establish a significant association between elevated Lp(a) levels (30
mg/dL) and CAD among African
Americans.1 14 15 16
The lack of understanding of this racial difference has made it
difficult to conclude with full confidence that Lp(a) is a risk factor
for CAD. In addition to high Lp(a) levels, the presence of small apo(a) isoforms has been associated with CAD in whites.17 18 19 20 21 22 23 24 In the majority of studies using high-resolution sizing techniques, small apo(a) size has been defined as <22 kringle 4 (K4) repeats.17 18 24 The majority of whites with high Lp(a) levels possesses at least 1 small apo(a) isoform; however, the majority of African Americans with high Lp(a) levels has no small apo(a) isoform.25 The high degree of correlation between elevated levels of Lp(a) and small apo(a) isoforms in whites makes it difficult to ascertain whether one is a confounder for the other regarding CAD. The lack of correlation between elevated levels of Lp(a) and small apo(a) isoforms in African Americans indicates that the independent contributions of high Lp(a) levels and small apo(a) isoforms could be tested in this ethnic group. To explore the hypothesis that CAD was associated specifically with the presence of an elevated level of Lp(a) with a small apo(a) isoform, we compared Lp(a) levels, apo(a) sizes, and the level of Lp(a) particles carrying small apo(a) sizes in African American and white patients undergoing coronary angiography.
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Methods |
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Additional information is available in the expanded Methods section available online at http://atvb.ahajournals.org.
Subjects
A total of 648 patients (401 men and 247 women)
ethnically self-identified as African American (n=232), white (n=344),
or other (n=72), scheduled for diagnostic coronary
arteriography at either Harlem Hospital Center in New York City or the
Bassett Hospital in Cooperstown, NY, were enrolled. The present
report is based on the findings in 572 African Americans and
whites.
Measurements of Lipids and Lipoproteins
Serum triglycerides and total and HDL
cholesterol were determined by using a standard enzymatic
procedure, and LDL cholesterol was calculated. Lp(a) levels
were measured by using a method insensitive to size variation in apo(a)
(Sigma Diagnostics). Corrected LDL cholesterol
levels were calculated by adjusting for Lp(a)
levels.26 Elevated
Lp(a) levels were defined as 30 mg/dL (72
nmol/L).1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 18 19 20 21 22 23 24
Apo(a) Isoform Size Determination
Apo(a) isoform sizes were analyzed by
SDS–agarose gel electrophoresis followed by
immunoblotting.27
Apo(a) isoforms were classified as being either of small size (<22 K4
repeats) or large size (22 K4
repeats).17 18 19 20 21 22 23 24
To validate the apo(a) isoform size determination, we performed
genotyping of apo(a) allele sizes by pulsed field
electrophoresis.28
Overall, there was an excellent agreement between the phenotyping and
genotyping procedures (r=0.997).
In the majority of patients (n=323, 198 men and 125 women), 2 distinct apo(a) protein bands were detected. No apo(a) protein bands could be detected in 20 patients (13 men and 7 women) with Lp(a) concentrations <2.6 nmol/L (<1.1 mg/dL). In the remaining 229 patients (141 men and 88 women), a single apo(a) protein band was detected. Of the 552 subjects with detectable apo(a) isoforms, 473 (86%) carried exclusively large or exclusively small apo(a) isoforms, and there was no need for apportioning. In the 68 subjects carrying a large plus a small isoform, the relative contribution of small-isoform Lp(a) and large-isoform Lp(a) was based on the intensity of staining of the 2 bands. The relative intensity of each apo(a) isoform was multiplied by the total plasma Lp(a) level to compute the Lp(a) level associated with each apo(a) isoform.
Coronary Angiography
The coronary angiograms were read by 2
experienced readers blinded to patient identity, the clinical
diagnosis, and the lipoprotein results. The readers recorded the
location and extent of luminal narrowing for 15 segments of the major
coronary
arteries.29 The
presence of CAD was defined as the presence of at least 50%
stenosis in any 1 of 15 coronary artery segments. Of
the patients without CAD, the majority (80.5%) had <25%
stenosis, and of the patients with CAD, 81% had >75%
stenosis.
Statistical Analysis
Because the distribution of values for Lp(a) and
triglycerides were skewed, logarithmic transformations of
these data were performed before statistical analysis.
Comparisons of means between groups were made by the Student
t test. The Fisher exact test was used to calculate
the probability value for odds ratios (ORs) of the association of
univariate categorical data with case-control status.
Conditional logistic regression was used to assess the association with
case-control status for multivariate models. SAS was
used for all calculations.
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Results |
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Lp(a) levels were approximately twice as high in African Americans as in whites (P<0.0001) (Table 1
). Mean Lp(a) levels were higher in white patients
with CAD than in those without CAD (69.0±96.9 versus 47.1±59.7
nmol/L, respectively; P=0.01), whereas there was no
significant difference among African Americans (141.3±106.0 versus
120.5±90.6 nmol/L for patients with and without CAD, respectively;
P=NS). The difference among whites was due to higher
Lp(a) levels among men with CAD compared with men without CAD; mean
Lp(a) levels were 68.1±91.7 versus 39.7±49.2 nmol/L, respectively
(P=0.004). There was no significant difference in
Lp(a) levels among white women with or without CAD. Lipid and
lipoprotein levels for African Americans and whites with and without
CAD are shown in
Table 2.
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An inverse relationship between apo(a) sizes and plasma
Lp(a) levels in both ethnic groups was observed. In African Americans,
median Lp(a) levels gradually declined from small to large apo(a)
sizes, whereas in whites, median Lp(a) levels declined abruptly for
apo(a) sizes of >21 K4 repeats
(Figure).
Large apo(a) isoform sizes were more prevalent among African Americans
than among whites with elevated Lp(a) levels (72 nmol/L,
corresponding to 30 mg/dL). Of subjects with elevated Lp(a), 80% of
whites (72 of 90) but only 26% of African Americans (40 of 157)
carried at least 1 small apo(a) isoform (<22 K4 repeats). This pattern
was similar among men and women.
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We evaluated the association between CAD and elevated Lp(a)
levels as well as between CAD and the presence of a small apo(a)
isoform in the 4 different sex/ethnicity groups. There was a borderline
association (P=0.057, OR 2.0) between elevated Lp(a)
levels and CAD
(Table 3) among white men but not women. In contrast, there
was no significant association between elevated Lp(a) levels and CAD
among African Americans irrespective of sex. The presence of at least 1
small apo(a) isoform was associated with CAD in white men
(P=0.043, OR 2.0;
Table 3). Although the OR for this association was similar
in African American men (OR 2.0), it did not reach significance. In
women, independent of ethnicity, there was no association between the
presence of a small size apo(a) and CAD.
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We considered how the amount of Lp(a) that was associated
with specific sizes of apo(a) isoforms varied with the presence of CAD.
As shown in the
Figure
,
the median Lp(a) level associated with smaller apo(a) isoform sizes was
markedly higher in patients with CAD than in patients without CAD for
African Americans and whites. In contrast, median Lp(a) levels
associated with large apo(a) isoform sizes were similar in patients
with or without CAD in both ethnic groups. It is clear from the figure
that irrespective of ethnicity, median levels for cases and controls
diverged for small apo(a) isoforms and converged for larger apo(a)
isoforms. Elevated levels of small-isoform Lp(a) were significantly
associated with CAD in white and African American men
(P<0.01, ORs 3.0 and 4.3, respectively;
Table 3). There was no significant association between
elevated small-isoform Lp(a) levels and CAD in women. (For details,
please see www.ahajournals.org.) These results strongly suggest that
the level of Lp(a) particles carrying small apo(a) isoforms predicts
the association between Lp(a) and CAD found in men. In contrast,
elevated large-isoform Lp(a) levels were not associated with CAD in any
sex/ethnicity group (ORs 0.7 to 2.0 in the 4 groups, respectively;
P=NS in all).
We next determined which of the 3 factors, ie, elevation of
Lp(a) levels, the presence of a small apo(a) isoform, or elevated
levels of small-isoform Lp(a), was the best predictor of CAD in white
men (the only sex/ethnicity group for which all 3 factors were
associated separately with CAD). (For details, please see
www.ahajournals.org.) In summary, the elevation of small-isoform Lp(a)
levels, ie, the subset of Lp(a) particles carrying a small apo(a)
isoform, was a more significant risk factor for CAD than either the
elevation of Lp(a) levels or the presence of a small apo(a) isoform.
Among African American men, elevated levels of small-isoform Lp(a) was
the only one of these variables significantly associated with CAD
(Table 3). Thus, independent of race/ethnicity, an elevated
small-isoform Lp(a) level was associated with CAD in men. In contrast,
small-isoform Lp(a) was not associated with CAD among women. When
analyzing all subjects together, we found a significant interaction
between elevated small-isoform Lp(a) levels and sex
(P<0.03), supporting these findings. In sex-specific
analysis, there was no significant interaction between elevated
small-isoform Lp(a) levels and ethnicity.
To determine the extent of confounding of the association between CAD and elevated small-isoform Lp(a) levels by other risk factors, we performed conditional logistic regression with a model controlling for age, race/ethnicity, diabetes, hypertension, smoking, and plasma concentrations of small-isoform Lp(a), HDL cholesterol, LDL cholesterol corrected for cholesterol content of Lp(a), and logarithmically transformed triglycerides. When controlling for these factors, we found that elevations of small-isoform Lp(a) remained highly significantly associated with CAD for all men (P=0.0001, OR 4.8). Significant associations of CAD with small-isoform Lp(a) were also found when African American and white men were analyzed separately (OR 4.3 [P<0.03] and OR 5.8 [P<0.001], respectively).
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Discussion |
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We demonstrate a significant association between CAD and elevated levels of small-isoform Lp(a), ie, elevated levels of Lp(a) particles with small apo(a) isoforms, in African American and white men. To our knowledge, this is the first study demonstrating a significant association between Lp(a) and CAD in African Americans. We suggest that the failure to observe an association between Lp(a) and CAD in African Americans in other studies15 30 reflects analysis of the relationship between either Lp(a) levels or apo(a) size with CAD, without taking into consideration the level of Lp(a) associated with different apo(a) isoforms.
The possibility that size variation of apo(a) could be associated with cardiovascular disease has been raised in previous studies, although the results have been inconsistent.7 17 18 19 20 21 22 23 24 31 32 33 In several of these studies, only a limited number of apo(a) size isoforms were resolved.22 23 32 Subsequently, a high-resolution technique allowing separation of >34 differently sized apo(a) isoforms was introduced.27 34 This was used in the present study, and the distribution of Lp(a) levels across apo(a) sizes was in good agreement with previous findings in normal healthy African Americans and whites.25 Of note, even with the higher resolution of apo(a) isoforms, we did not see an association of apo(a) size alone with CAD in African Americans.
Our findings indicate that it is important to take apo(a) sizes and the level of Lp(a) associated with each apo(a) isoform into account when assessing CAD risk. Therefore, the presence of 2 circulating apo(a) isoform sizes in the majority of all individuals presents a challenge. We determined the level of Lp(a) associated with specific apo(a) sizes on the basis of independent measures of Lp(a) levels and the intensity of apo(a) bands. We recognize the possibility of bias in apportioning Lp(a) levels. However, our classification of apo(a) sizes as being either of small or large size served to minimize the need for apportioning Lp(a), because this was required in only 14% of the patients.
We found that the level of Lp(a) particles with isoform
sizes of <22 K4 repeats was higher in patients with CAD
(Figure).
In exploratory analyses, as when different cutoff levels were
used in the present study (<21, <22, <23, or <24 K4 repeats),
the ORs for CAD were not substantially affected (ORs 2.9 to 4.3,
P<0.005 for men). Our studies suggest that the level
of Lp(a) associated with small-sized apo(a) constitutes a risk factor
and, therefore, that small apo(a) is atherogenic. Although our results
broadly implicate small-sized apo(a) as being atherogenic, further
mechanistic studies are needed to address this issue in more
detail.
Although the frequency of subjects carrying at least 1 small
isoform was comparable in African Americans and whites (21% and 29%,
respectively), 
80% of whites but only 26% of African Americans
with elevated Lp(a) had at least 1 small apo(a) isoform. Because most
whites with elevated Lp(a) carry small apo(a) sizes, it is difficult in
this ethnic group to ascertain the relative contribution to the risk
for CAD of small apo(a) size on one hand and elevated Lp(a) levels on
the other. In contrast, African Americans have elevated Lp(a) over a
wider range of apo(a) isoforms. Our results are consistent with
previous studies demonstrating that in African Americans, neither the
elevation of Lp(a) levels nor the presence of small apo(a) isoforms
alone was significantly associated with
CAD.15 30
However, our demonstration that the combination of elevated Lp(a)
levels and small apo(a) size was associated with CAD in African
American and white men provides the first experimental evidence
supporting previous suggestions that ethnic differences in the
relationship between apo(a) isoform size and Lp(a) levels may have an
impact on the use of Lp(a) level as a risk
factor.20 25
Thus, an elevated Lp(a) level is a poor surrogate marker for the
relevant risk factor, ie, high levels of small-isoform Lp(a), in
African Americans, but the strong association in whites between
elevated Lp(a) and small apo(a) size makes elevated Lp(a) levels a
reasonable surrogate marker in this group for elevated small-isoform
Lp(a). However, also among whites in whom high Lp(a) levels are carried
by large apo(a) isoforms, the use of Lp(a) levels to estimate CAD risk
may be less accurate. Therefore, a measurement based on Lp(a) levels
along with apo(a) sizes may be the optimal way to assess risk for CAD
independent of ethnicity.
We recognize the limitations of the present study, which was designed as a cross-sectional and not a prospective study. However, differences between the various sex/ethnicity groups regarding serum lipids and lipoproteins, including Lp(a) levels, were similar to previous findings in large population groups (results not shown). In addition, established risk factors, such as total and LDL cholesterol levels, were significantly higher among patients with CAD in both ethnic groups. Although patients classified as being without CAD in general had a low degree of stenosis, the presence of coronary atherosclerosis to at least some extent cannot be excluded. Therefore, further prospective studies are needed to extend these findings to the general population.
An interesting observation in the present study was the lack of association between elevated Lp(a) levels, small apo(a) size, or elevated small-isoform Lp(a) levels with CAD in women. Although studies simultaneously addressing apo(a) size and Lp(a) levels in relation to CAD are scarce in women, an elevated Lp(a) level is a risk factor in women.4 8 35 However, our results suggesting a sex difference regarding the association of small-isoform Lp(a) with CAD are in good agreement with another study in a largely white population.7 Several factors could contribute to this sex difference. First, the extent of stenosis in a coronary artery, as judged by angiography, may not be equally representative of CAD in both sexes.36 Second, because estrogen affects Lp(a) levels, hormonal effects could cloud an association between Lp(a) and CAD.37
In conclusion, the present study, the first to evaluate the level of Lp(a) associated with specific apo(a) sizes as a risk factor for CAD, provides new insights into the role of Lp(a). First, our results conclusively demonstrate that the combination of high Lp(a) levels and small-sized apo(a) is a risk factor in white and African American men. Second, our findings suggest that the absence of association between Lp(a) and CAD in African Americans in previous studies is not due to a difference in the atherogenicity of Lp(a) across race/ethnicity but is a consequence of race/ethnicity differences in the distribution of Lp(a) levels across apo(a) sizes. Thus, the present study lays to rest the notion that Lp(a) is not a risk factor for CAD in African Americans, an issue that until now has been controversial. Finally, our results raise the possibility that small-isoform Lp(a) is the atherogenic subpopulation of Lp(a) particles that determines the degree of risk associated with any level of Lp(a). Further studies on the atherogenicity of small-isoform Lp(a) are needed.
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Acknowledgments |
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This project was supported by grants 49735 and 62705 from the National Heart, Lung, and Blood Institute. Dr Berglund was an Established Scientist of the American Heart Association, New York City Affiliate. We acknowledge the indispensable role of Jay Brown, MD, of Harlem Hospital Center, who, before his untimely death, committed his energies and enthusiasm to the early stages of implementation of this project and ensured a successful foundation for this work.
Received April 7, 2000; accepted September 20, 2000.
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