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Articles |
1
Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center and Tufts University School of Medicine, 750 Washington St., Boston, MA 02111.
2
Lipid Metabolism Laboratory, Jean Mayer US Department of
Agriculture Human Nutrition Research Center on Aging at Tufts
University, Boston, MA 02111.
3
Department of Epidemiology and Biostatistics, Boston
University School of Public Health, Boston, MA 02118-2394.
4
Framingham Heart Study, National Institutes of Health,
National Heart, Lung, and Blood Institute, Framingham, MA
01702.
a Address correspondence to this author at: New England Medical Center, Box 216, 750 Washington St., Boston, MA 02111.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: We measured plasma Lp(a)-cholesterol [Lp(a)-C] in a Caucasian population of offspring and spouses of the Framingham Heart Study participants, using a lectin-based assay (LipoproTM). We compared the prevalence of increased Lp(a)-C to the presence of sinking pre-ß-lipoprotein (SPB). We also related Lp(a)-C concentrations to the prevalence of CHD risk in the entire population.
Results: The mean (± SD) Lp(a)-C concentration in the Framingham
population (n = 3121) was 0.186 ± 0.160 mmol/L, with no
significant gender or age differences. The mean Lp(a)-C concentrations
in the absence or presence of SPB were 0.158 ± 0.132 mmol/L and
0.453 ± 0.220 mmol/L, respectively (P <0.0001).
The mean Lp(a)-C concentration in men with CHD (n = 156) was
0.241 ± 0.204 mmol/L, which was significantly (P
<0.001) higher, by 34%, than in controls. The odds ratio for CHD risk
in men with Lp(a)-C 
0.259 mmol/L (10 mg/dL), after adjusting for
age, HDL-cholesterol, LDL-cholesterol, smoking, diabetes, blood
pressure, and body mass index, was 2.293 (confidence interval,
1.55–3.94; P <0.0005). Lp(a)-C values correlated
highly with a Lp(a)-mass immunoassay [ApotekTM
Lp(a); r = 0.832; P <0.0001; n
= 1000].
Conclusions: An increased Lp(a)-C value 0.259 mmol/L (10
mg/dL) is an independent CHD risk factor in men with a relative risk of
more than 2, but was inconclusive in women. Lp(a)-C measurements offer
an alternative to Lp(a)-mass immunoassays and can be performed on
automated analyzers.© 1999 American Association for Clinical
Chemistry
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Apolipoprotein (a) [apo(a)] is known to be a very heterogeneous glycoprotein that shares at least 75% homology with plasminogen, including domains of plasminogen referred to as kringle 4, kringle 5, and the protease domain. There is no unique domain of the apo(a) gene that does not share homology with plasminogen (2). apo(a) is highly glycosylated (3)(4), with numerous O-glycosidic linkages in the regions between the kringle domains (5). At least 34 phenotypes are expressed, ranging from 12 to 50 kringles (6)(7), and there are potentially more phenotypes and genotypes that may exist.
Increased Lp(a) concentrations have been described in numerous case-control studies as correlating with coronary heart disease (CHD) (8)(9)(10)(11)(12)(13)(14)(15). There have been several prospective studies that have identified Lp(a) as a CHD risk factor (16)(17)(18)(19)(20)(21)(22)(23)(24)(25), although not all have been positive (26)(27)(28)(29). The measurement of Lp(a) mass has been the "standard" since the formulation of the first radioimmunoassay by Albers and Hazzard (30) in 1974. Because of variability in apo(a) isoform size, we do not believe that Lp(a) should be standardized on the basis of mass concentrations. Immunoassays may not provide an accurate measure of Lp(a) concentration if the antibodies in the assay bind to epitopes that may be present in apo(a) in multiple copies or if a single epitope within apo(a) is altered by conformational changes because of large variations in apo(a) size. Marcovina et al. (31) have reported that an isoform size bias, which misrepresents the true Lp(a) concentration, can occur with some assays, although this is less of a problem with other assays (31)(32).
Three prospective studies that measure Lp(a) as sinking pre-ß-lipoprotein (SPB) (19)(20)(21) strongly support Lp(a) as an important CHD risk factor. The method used in those studies may be reliable, in part, because of its lack of reliance on immunodetection, its dependence on lipid detection, and its measurement of fresh plasma samples, rather than frozen, archived samples. However, SPB analysis is only semiquantitative.
A novel assay has been designed to avoid the difficulties that may arise with immunodetection of various isoforms of apo(a) by nonspecifically trapping Lp(a) with a lectin, and then measuring the cholesterol in the lectin-bound fraction using standard enzymatic cholesterol assays, standardized to a lower range of detection [0–1.297 mmol/L (0–50 mg/dL)]. This method has been described, characterized, and shown to correlate highly with an immunoassay (MacraTM; Wampole Laboratories) (33). To further evaluate Lp(a)-cholesterol [Lp(a)-C] as a CHD risk factor, we measured Lp(a)-C in plasma samples collected from participants in the Framingham Offspring Study between 1990 and 1994 and compared them to SPB results generated on the same subjects between 1970 and 1974 (19)(20). It is well documented that there are no significant changes in Lp(a) concentrations over time (34), although cross-sectional data suggest some small effect (35). In addition, we compared the results of Lp(a)-C analysis in a subset of 1000 subjects with Lp(a)-mass values generated with the ApotekTM Lp(a) Assay (Sigma).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SPBs were obtained using methods described previously (19)(20). In brief, fresh plasma samples were collected from subjects, ultracentrifuged to remove VLDL (d <1.006 kg/L), and immediately blotted onto cellulose acetate strips, which were then applied to an electrophoresis apparatus containing barbital buffer. Samples were then subjected to 1.5 V/cm for 16 h. The cellulose acetate strips were then stained with oil red O. Samples were then all read at the same time, using the same reader (WPC), and classified as "positive", "trace", or "not present".
To compare Lp(a)-C results directly to Lp(a)-mass concentrations, plasma samples from a subset of 1000 Framingham Offspring Study participants were also subjected to Lp(a)-mass measurement with the Apotek Lp(a)-mass assay, an immunoassay that traps Lp(a) with a polyclonal antibody to apo(a) and detects with polyclonal antibodies to apolipoprotein B, making the assay less likely to be affected by changes in isoform size. The assay was performed according to the package insert instructions, and the results have been published elsewhere (32).
Other plasma lipoproteins were determined as described previously (36). Total cholesterol was measured on an Abbott Spectrum CCX, using the cholesterol esterase/cholesterol oxidase method (Sigma), according to the package insert. Triglycerides were also measured using this automated method, measuring glycerol after hydrolysis, according to package insert specifications (Sigma). HDL-cholesterol (HDL-C) was determined using Mg2+/dextran precipitation of lipoproteins containing apolipoprotein B, followed by cholesterol measurement of the unprecipitated HDL fraction, using a standard cholesterol esterase/cholesterol oxidase assay. LDL-cholesterol (LDL-C) was calculated using the formula developed by Friedewald et al. (37) for subjects with triglycerides <4.0 g/L (<400 mg/dL).
All prevalent CHD cases were identified at or before exam 5 (through 1995). A panel of three physicians examined the records of all potential CHD cases and confirmed the presence of CHD according to the criteria established for the analysis of the Framingham Heart Study, as described elsewhere (38). CHD includes angina pectoris, myocardial infarction, coronary insufficiency, and coronary death. No cases were prospectively identified.
The statistics were analyzed using the SAS program (SAS Institute).
Subjects with prevalent CHD were compared with those with no evidence
of CHD on a variety of known risk factors, including hypertension,
diabetes, smoking history, LDL-C, HDL-C, and triglycerides as well as
Lp(a)-C, SPB, and Lp(a) mass. A corrected LDL-C was calculated by
directly subtracting Lp(a)-C from LDL-C. The Student t-test
was used to compare the mean values of continuous measures. A
2 test was calculated for categorical factors.
We log-transformed highly skewed continuous measures to normalize the
distribution before assessing them in a comparison between subjects
with and without CHD. Although the untransformed means and standard
deviations were reported, P values for the analyses of the
transformed variables were reported. To evaluate the relationship
between Lp(a)-C and SPB, different percentiles of Lp(a)-C were compared
with the presence of SPB (both borderline present and present). The
approximate 75th percentile for Lp(a)-C (0.259 mmol/L) was chosen as a
cutoff point because this is the approach taken by the National
Cholesterol Education Program for LDL-C. The sensitivity and
specificity for Lp(a) were calculated using SPB as the
reference; thus the sensitivity was the proportion of
SPB-positive subjects who had Lp(a) 0.259 mmol/L, and the specificity
was the proportion of SPB-negative subjects who had Lp(a) <0.259
mmol/L. To adjust for known risk factors for CHD, we used
logistic regression analysis for the presence or absence of prevalent
CHD at exam 5. Lp(a)-C was assessed both as a continuous variable and
by group analysis (less than or equal to, or greater than 0.259
mmol/L).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The characteristics of the Framingham Offspring Subjects are shown in
Table 1
and display the gender differences in this population. These
data obtained from the Framingham Heart Study provide normal
ranges for Lp(a)-C. There were no significant gender or age differences
in Lp(a)-C concentrations. The mean Lp(a)-C values were 0.186 ±
0.160 mmol/L (7.21 ± 6.15 mg/dL) in men and 0.182 ± 0.166
mmol/L (7.06 ± 6.42 mg/dL) in women, with an overall mean of
0.185 ± 0.163 mmol/L (7.13 ± 6.29 mg/dL). As noted in the
percentile distribution data in Table 2
, the Lp(a)-C values were highly skewed, with a skewness of 1.76
(1.65 in men and 1.86 in women) and a kurtosis of 3.80 (3.17 in men and
4.30 in women). The distribution patterns were consistent with the
distribution of Lp(a) mass seen in the Framingham population
(35) and other Caucasian populations, measured with
immunoassays (39).
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Lp(a)-mass results obtained with the Apotek Lp(a) assay for a subset of 1000 Framingham Heart Study participants were similarly skewed, with a skewness of 2.34 and a kurtosis of 9.42, a mean Lp(a) mass of 0.260 ± 0.295 g/L (25.97 ± 29.49 mg/dL), and no significant gender or age differences. Lp(a)-C was highly correlated with Lp(a) mass in both men and women (P <0.0001), with Pearson correlation coefficients for the log-transformed Lp(a)-C of 0.829 and 0.835, respectively. Despite the skewed distribution, differences in measurements (cholesterol vs mass), and the wider total population variance of the Lp(a)-mass values (SD, 113% of mean) when compared with Lp(a)-C (SD, 88% of mean), comparisons of all subjects at the 75th percentile [Lp(a) mass of 0.344 g/L and Lp(a)-C of 0.259 mmol/L] were similar, with 93% specificity and 82% sensitivity in men and 93% specificity and 85% sensitivity in women.
In men, Lp(a)-C had a curvilinear relationship with age, grouped by
decade (Table 3
), but failed to attain statistical significance. In women,
there was a linear relationship between Lp(a)-C and age delineated by
decade, with the largest difference in the fifth decade, when most
women reach menopause. Among the women, there also were differences in
Lp(a)-C values that were dependent on menopausal status (Table 4
). When pre- and postmenopausal women were compared, only
16.27% of premenopausal women had Lp(a)-C 0.259 mmol/L, compared
with 26.73% of postmenopausal women (P <0.001). Because
menopause is an age-related phenomenon, it is difficult to separate the
effect of age from menopause. When compared with men, women (Table 3
)
had a much larger gradation of Lp(a)-C values across increasing
decades, which was sustained after the fifth decade, whereas in men,
the gradation decreased dramatically after the sixth decade.
Furthermore, an estrogen effect was supported by the 17.6% lower mean
Lp(a)-C concentrations (P <0.01) in women without CHD and
receiving hormone replacement therapy [HRT; Lp(a)-C, 0.155 ±
0.150 mmol/L (5.98 ± 5.79 mg/dL); n = 281] compared with
women the same mean age (55 ± 10 years) without CHD and not
receiving HRT [Lp(a)-C, 0.188 ± 0.170 mmol/L (7.26 ± 6.57
mg/dL); n = 1284].
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SBP measurements of Lp(a) were performed in this population and have
been reported elsewhere to predict the risk of CHD in men <55 years
(20) and in women >55 years (19). Numerous
studies, reviewed by Bostom et al. (20), have demonstrated
that the presence of an SPB band corresponds to Lp(a) and is highly
specific for Lp(a)-mass concentrations of 0.3 g/L (30 mg/dL) or more.
SPBs were reported as being "present", "borderline present", or
"not present". A comparison of the mean Lp(a)-C concentrations for
these three categories is shown in Table 5
and clearly shows a gradation from the absence of SPB
[0.157 ± 0.131 mmol/L (6.08 ± 5.06 mg/dL)] to borderline
present [0.359 ± 0.209 mmol/L (13.89 ± 8.06 mg/dL)] to
present [0.453 ± 0.0.221 mmol/L (17.49 ± 8.54 mg/dL)],
with very little overlap between the categories "absent" and
"present". Subjects with Lp(a)-C concentrations 0.259 mmol/L
(10 mg/dL) are 11.6 (odds ratio) times more likely to have a SPB band
(present or borderline) than subjects with Lp(a)-C concentrations
<0.259 mmol/L (P <0.0002). The sensitivity and specificity
with SPB as the reference are 72.1% and 81.8%, respectively.
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The mean Lp(a)-C concentrations in men and women with and without CHD
are compared in Table 6
. There was a statistically significant difference between men
with CHD [0.241 ± 0.166 mmol/L (9.32 ± 7.87 mg/dL)] and
men without CHD [0.180 ± 0.152 mmol/L (6.96 ± 5.87 mg/dL);
P < 0.001]. On the other hand, there was no
significant difference between women with CHD [0.199 ± 0.158
mmol/L (7.71 ± 6.10 mg/dL)] and women without CHD [0.182
± 0.166 mmol/L (7.03 ± 6.43)]. However, the prevalence of CHD
in women was only 3.5% (68 cases out of 1633 subjects), compared with
10.4% (156 cases out of 1488 subjects) in men (see Table 1
) in this
cohort, which was relatively young (55 ± 10 years) for assessing
CHD in women.
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Logistics regression analysis (Table 7
) for the association of Lp(a)-C with CHD was performed, using
Lp(a)-C as a continuous variable and grouping Lp(a) 0.259 mmol/L
(10 mg/dL), to compare the indicator that best correlated with
the presence (present and borderline present) of SPB. The relative odds
of CHD attributable to increased Lp(a)-C were adjusted for age, LDL-C,
HDL-C, smoking, diabetes, blood pressure, and body mass index.
The Lp(a)-C values were log-transformed to better normalize the
distribution of this highly skewed indicator. As a continuous variable,
Lp(a)-C in men had an odds ratio of 1.483 [95% confidence interval
(CI), 1.186–1.854; P <0.0005] for each unit increase on a
log scale, whereas the odds ratio of 1.102 was not significant (95%
CI, 0.824–1.437) in women. To better isolate Lp(a)-C and LDL-C [which
contains LDL and intermediate-density lipoprotein as well as
Lp(a)-C], the analysis was repeated with a corrected LDL-C (LDL-C
minus Lp(a)-C). Pearson correlation coefficients showed a significant
correlation between LDL-C and Lp(a)-C in men (r
=0.146; P = 0.0001), which disappeared when
analysis was repeated with the LDL-C corrected for Lp(a)-C
(r = -0.028; P = 0.2935). The
logistics regression analysis with corrected LDL-C values was slightly
lower than with the uncorrected LDL-C values, but with tighter
confidence intervals (Table 7
). To compare the Lp(a)-C indicators that
match SPB, the same adjusted analysis for Lp(a)-C 0.259 mmol/L (10
mg/dL) in men yielded an odds ratio of 2.293 (95% CI, 1.549–3.94;
P <0.0001). Again, a repeat analysis with corrected LDL-C
values yielded a slightly lower odds ratio, but with tighter confidence
limits (Table 7
). However, the odds ratio was not significant in women,
with a value of 0.760 (95% CI, 0.390–1.481). The use Lp(a)-C values
as a surrogate for SPB, a measurement of Lp(a) that confers
attributable risk of CHD, yields similar results as previously
published SPB prevalence data in men.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The direct comparison of Lp(a)-C to SPB values provides indicators that
are believed to predict the relative risk of CHD in both men and women.
The odds ratio of 11.6 for Lp(a)-C 0.259 mmol/L (10 mg/dL) to be
found in subjects with the presence of SPB, with a sensitivity of
72.1% and a specificity of 81.8%, supports the similarities of these
two measurements of Lp(a). Both of these methods are dependent on the
detection of the lipid content of Lp(a), rather than an immunodetection
method. Prevalence data support the use of Lp(a)-C 0.259 mmol/L (10
mg/dL) in predicting CHD risk in men, whereas the data are less clear
for women. However, the prevalence of CHD in this population of women
was only 3.5% (68 cases), whereas the prevalence of CHD in men was
10.4% (152 cases). Lp(a)-C will need to be assessed prospectively in
this population to determine the true relative risk of CHD in both men
and women.
The results in women may be further confounded by the effect of estrogen status on Lp(a)-C concentrations. Although Jenner et al. (35) demonstrated that Lp(a)-mass values corrected for age were not different in pre- and postmenopausal women, menopause is an age-related phenomenon that cannot be clearly separated from this indicator. To support this further, our study provides evidence that when women receiving HRT are compared with women of the same age not receiving estrogen, there is a 17.6% difference in the mean Lp(a)-C between these two groups. Furthermore, a comparison of Lp(a)-C mean concentrations by decade demonstrates a continuous upward gradation that is sustained in women beyond the fifth decade, but falls in men beyond the sixth decade. The effect of estrogen status on Lp(a)-C is further supported by the work of Kim et al. (40), who reported a 23% reduction in Lp(a) mass in postmenopausal women placed on HRT (conjugated equine estrogens, 0.625 mg/day, and medroxy progesterone acetate, 2.5 mg/day); when HRT was discontinued, the concentration of Lp(a) mass returned to normal (41).
In summary, this analysis in the offspring and spouses of the
Framingham Heart Study establishes normal ranges of Lp(a)-C for men and
women. Our analysis confirms a similarly skewed distribution pattern of
Lp(a)-C values when compared with those we reported in another
publication (35), using another commercially available
immunoassay (Macra). The Lp(a)-C values correlated highly with Apotek
Lp(a) mass and with the presence or absence of SPB. However, in
contrast to SPB, the Lp(a)-C assay provides a quantitative measure. Our
data indicate that a Lp(a)-C concentration 0.259 mmol/L (10 mg/dL)
is a useful tool in predicting the risk of CHD in men. Regarding CHD
risk, the relationship between Lp(a) and LDL-C, which was first
reported by Armstrong et al. (42), is likely because of the
presence of Lp(a)-C in the LDL-C value; this relationship can be
directly removed from the analysis by subtracting Lp(a)-C from LDL-C
when using the Lipopro Lp(a)-cholesterol assay. Lp(a)-C measurements
provide useful information for CHD risk assessment. In assessing the
risk of Lp(a)-C, especially in analyses that compare it with LDL-C, it
may be appropriate to use a corrected LDL-C to isolate Lp(a)-C from the
LDL-C value. It would be inappropriate to always correct LDL-C, because
most LDL-C measurements include cholesterol from LDL,
intermediate-density lipoprotein, and Lp(a). Moreover, the Lp(a)-C
method may be easier to standardize, both nationally and
internationally, than immunoassay methods.
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Acknowledgments |
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Footnotes |
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References |
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J. Ordonez-Llanos, A. M. Wagner, R. Bonet-Marques, J. L. Sanchez-Quesada, F. Blanco-Vaca, and F. Gonzalez-Sastre Which Cholesterol Are We Measuring with the Roche Direct, Homogeneous LDL-C Plus Assay? Clin. Chem., January 1, 2001; 47(1): 124 - 126. [Full Text] [PDF]
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N. S. Haque, J. T. Fallon, M. B. Taubman, and P. C. Harpel The chemokine receptor CCR8 mediates human endothelial cell chemotaxis induced by I-309 and Kaposi sarcoma herpesvirus-encoded vMIP-I and by lipoprotein(a)-stimulated endothelial cell conditioned medium Blood, January 1, 2001; 97(1): 39 - 45. [Abstract] [Full Text] [PDF]
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M. von Depka, U. Nowak-Gottl, R. Eisert, C. Dieterich, M. Barthels, I. Scharrer, A. Ganser, and S. Ehrenforth Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism Blood, November 15, 2000; 96(10): 3364 - 3368. [Abstract] [Full Text] [PDF]
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N. S. Haque, X. Zhang, D. L. French, J. Li, M. Poon, J. T. Fallon, B. R. Gabel, M. B. Taubman, M. Koschinsky, and P. C. Harpel CC Chemokine I-309 Is the Principal Monocyte Chemoattractant Induced by Apolipoprotein(a) in Human Vascular Endothelial Cells Circulation, August 15, 2000; 102(7): 786 - 792. [Abstract] [Full Text] [PDF]
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M. Nauck, W. Marz, and H. Wieland Is Lipoprotein(a) Cholesterol a Significant Indicator of Cardiovascular Risk? Clin. Chem., March 1, 2000; 46(3): 436 - 437. [Full Text] [PDF]
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