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Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies

^a Author for correspondence. Fax 207-883-1527; e-mail wcraig{at}fbr.org.

	Abstract

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Although in vitro studies support a pathophysiologic role for lipoprotein(a) [Lp(a)] in the development of atherosclerosis, and retrospective studies consistently report that there is a relationship between Lp(a) and ischemic heart disease (IHD), the conclusions drawn from prospective studies about this relationship have been inconsistent. To address this issue, we have performed a metaanalysis of data available from prospective studies. Lp(a) concentrations expressed as mass units vary markedly between studies, reflecting the need for assay standardization. In 12 of 14 prospective studies, Lp(a) concentrations are higher in subjects who later develop IHD (cases) than in those who do not (controls), although there is variation in the size of the effect. Sample storage temperature may contribute to this variability. When the studies are analyzed collectively, Lp(a) concentrations are significantly higher in cases than in controls, and the extent of the effect is similar in men and women. These findings provide evidence in support of a causal role for Lp(a) in the development of atherosclerosis. Measurement of Lp(a) may be useful to guide management of individuals with a family history of IHD or with existing disease. The separation in values between cases and controls is not, however, sufficient to allow the use of Lp(a) as a screening test in the general population.

	Introduction

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The role of lipoprotein(a) [Lp(a)] as a risk factor for ischemic heart disease (IHD) has received considerable attention in recent years. Lp(a) resembles the LDL particle in structure. Apolipoprotein B is the major apolipoprotein associated with LDL; in Lp(a), however, an additional apolipoprotein, apolipoprotein(a), is bound covalently to apolipoprotein B (1). The physiology and function of Lp(a) are still poorly understood, but the apolipoprotein(a) molecule demonstrates high sequence homology (75–90%) with plasminogen (2). This suggests that Lp(a) might contribute to the thrombotic, as well as to the atherogenic, aspects of IHD (3).

Retrospective studies, in which subjects with existing disease were compared with matched controls, have consistently shown an important association between increased concentrations of Lp(a) and IHD. Subjects in these studies have included survivors of myocardial infarction (4)(5), patients with symptoms of angina (6), and those with atherosclerosis confirmed by B-mode ultrasonography (7) or coronary angiography (8)(9). An association has also been demonstrated between Lp(a) concentrations and the severity of atherosclerosis, as quantitated by angiography (10).

Retrospective studies cannot distinguish whether Lp(a) is in the causative pathway or is increased for reasons secondary to the presence of disease. Since 1990, several prospective studies have addressed this issue, but with inconsistent results. Consequently, there remains uncertainty concerning both the relationship between Lp(a) and IHD and the utility of Lp(a) measurement in clinical practice (11)(12). We therefore performed a metaanalysis of the published prospective studies in an effort to resolve the uncertainty.

	Materials and Methods

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data collection
The following search strategy was used to identify relevant publications: Articles providing prospective data on the relationship between Lp(a) concentrations and IHD were identified by using a Medline CD-ROM search facility (database January 1991–August 1997, journals indexed through June 1997). Medical Subject Headings used in the search were "lipoprotein(a)" and "coronary artery disease"; the textword "prospective" was used to limit the reference lists produced by the initial search. The reference lists of these articles were then reviewed to identify additional sources, as were the reference lists of recent articles providing critical review of the Lp(a) epidemiologic literature (13)(14).

Data collected from identified studies included the age, sex, ethnicity, and clinical history of the participants. Studies were excluded if the study group included subjects with a history of IHD on entry, if subjects were preselected for a particular disease state that was itself associated with increased risk for IHD (15)(16), or if quantitative data were not available (17)(18)(19). Quantitative data on the number of subjects and respective serum or plasma Lp(a) concentrations for cases and controls were collected. Estimates of the mean, geometric mean, or median Lp(a) concentration for each subgroup were accepted for analysis; information on centiles or SD for the Lp(a) distribution in each group were also collected. Finally, data related to potential sources of heterogeneity were collected, including information on the type of Lp(a) assay used, the temperature of sample storage, and the length of sample storage.

data analysis
Lp(a) concentrations were expressed in mg/L; where necessary, original data were converted from mg/dL, IU/L, or nmol/L. Conversion from nmol/L to mg/L was performed using a molecular weight estimate for the apo(a) assay calibrator of 299.376 kDa (20). IU/L (21) was directly equivalent to mg/L.

The difference between cases and controls in each study was expressed as the ratio of Lp(a) concentration in cases divided by the Lp(a) concentration among controls [Lp(a) data were not transformed]. This approach provides a means of normalizing data between studies that use different Lp(a) assays, with different approaches to assay standardization. The case:control ratio is a robust estimate of the discriminatory power of Lp(a), assuming that the SD of the two population subgroups are similar between studies. Use of the Lp(a) case:control ratio also allows arithmetic mean Lp(a) data [not a satisfactory representation of the center of the highly skewed Lp(a) distribution] to be included, assuming that the shift in arithmetic means between cases and controls is proportional. The approach of pooling Lp(a) case:control ratio data makes the assumption that differences in Lp(a) concentrations between cases and controls are proportional between studies; proportional differences are typically seen when differences between assays are caused by problems with standardization. The Lp(a) case:control ratio should not be confused with odds or risk ratios; it simply expresses the ratio of Lp(a) concentrations between cases and controls before the development of IHD.

Log transformations were used where necessary. If not provided, log SD was calculated using either centiles of the Lp(a) distribution provided directly in the study (22)(23) or histograms provided in the study (24)(25)(26)(27)(29). In four studies (21)(28)(30)(32), it was not possible to estimate SD; therefore, a pooled estimate, weighted by the number of cases, was used. Because original data were not available, the log SD of the Lp(a) ratio was estimated from the central estimates and log SD of cases and controls, assuming certain conditions, using the method of Armitage and Berry (33), where:

Summary estimates of the effect [as Lp(a) case:control ratio] were calculated from the individual Lp(a) case:control ratios and the log SDs of their distributions, using published methodology (34) that included a formal test of heterogeneity. This method weights the estimate from each study by the inverse of a combination of within- and among-study variances. Analyses were performed using a statistical software package from BMDP Statistical Software, Inc.

	Results

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Five prospective studies were excluded from the analysis. Three of these were excluded because the Lp(a) data were qualitative rather than quantitative (17)(18)(19) (all of these qualitative studies demonstrated positive relationships between Lp(a) and IHD risk). The other two were excluded because populations with disease states predisposing to atherosclerosis (renal disease and diabetes mellitus) were studied (15)(16). In addition, one of these latter studies did not provide data on the age and sex of study subjects (16), and the other included subjects with prior history of IHD at entry (15). The studies included were either cohort (21)(23)(32) or nested case-control (22)(24)(25)(26)(27)(28)(29)(30)(31), with a median of 8 years follow-up. In all but one study (31), which was restricted to fatal IHD, the clinical endpoints measured were both fatal and nonfatal IHD. Controls were defined as subjects who did not develop IHD during the follow-up periods. Study subject ethnicity was provided by two studies, both from the United States (26)(27). In both of these studies, the populations were ~95% Caucasian. Given that the countries of origin for the other studies were in Northern European, it is reasonable to assume that nearly all study subjects were Caucasian. Demographic data, sample management, and assay protocols are summarized in Table 1 . Data were available for females in 3 studies and for males in 11; study subjects were generally middle-aged. Lp(a) assays were performed by four different methodologies, and with the exception of one study (32), samples were stored between 1 and 18 years at -20 to -90 °C.

Quantitative Lp(a) data are shown for cases and controls in Table 2 . Data from 1617 cases (190 females and 1427 males) and 10 035 controls (357 females and 9678 males) were available for analysis. There was marked variation in Lp(a) concentrations between studies, even after conversion to the same units [median Lp(a) concentrations in controls ranged from 64 to 288 mg/L]. This variation [45-fold for all studies and 6-fold when the two most discrepant studies (27, 29) are excluded] highlights the need for an additional normalization step before combining data between studies.

Fig. 1 shows the Lp(a) case:control ratios and 95% confidence intervals for each study. There was a positive association of the combined estimate with IHD risk [Lp(a) case:control ratio 1.40 (95% confidence interval, 1.22–1.57)]. This relationship was similar between males [1.42 (1.21–1.63)] and females [1.32 (1.19–1.45)]. There was considerable variability in Lp(a) case:control ratios (range, 0.68–2.00); the heterogeneity observed was highly significant ( = 901, P <0.001). The age of study subjects, the length of follow-up, the length of sample storage, and sample storage temperature were investigated as potential sources of the observed heterogeneity. The storage temperature demonstrated the strongest relationship with Lp(a) case:control ratio (r = -0.44, n = 13, P = 0.13). Thus, lower freezer temperatures correlated with a higher point estimate for the Lp(a) case:control ratio.

View larger version (18K): [in this window] [in a new window]   Figure 1. Individual and combined estimates for the Lp(a) case:control ratio, with 95% confidence intervals, for all studies included in the present analysis. The data are sorted first by gender and then by Lp(a) case:control ratio. For the combined estimates, information is provided on the number of cases (top) and the point estimate for Lp(a) case:control ratio (bottom). Numbers on the x-axis refer to the study citation number, as listed in References. The horizontal dotted lines illustrate the relationship between combined estimates and the estimates for the individual studies.

Of the 12 studies included in the analysis, 9 provided a dose–response analysis of the relationship between Lp(a) and IHD risk. Among these studies, six showed evidence of a positive dose–response effect (21)(23)(26)(28)(31)(32), one was equivocal (30), and two found no dose–response effect (22)(25) (Table 3 ). Among studies that found Lp(a) to be a positive prospective risk factor for IHD, seven tested the independence of this effect by adjustment of data for coexisting risk factors (21)(23)(26)(27)(29)(30)(31). Although the specific covariates examined differed between studies, in no case did adjustment for age, blood pressure, body mass index, smoking, or lipoprotein-related variables eliminate the significant relationship between Lp(a) and IHD risk

	Discussion

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The present metaanalysis documents that Lp(a) is an independent prospective risk factor for IHD. This finding, together with evidence for a dose–response relationship between Lp(a) and IHD, provides support for a causative role for Lp(a) in the pathogenesis of atherosclerosis. Data from in vitro studies, which suggest a role for Lp(a) in both atherogenesis and thrombogenesis (3), also support this conclusion by providing evidence for pathophysiologic mechanisms to explain the relationship between Lp(a) and IHD. Additional primary data are needed before metaanalysis can be used to determine whether the atherogenicity of Lp(a) is modulated by coexisting factors. In the course of this analysis, we noted at least a sixfold variation in reported Lp(a) concentration, which clearly presents an issue for interlaboratory communication and highlights the need for assay standardization. Even with this problem, however, the studies were mostly consistent with respect to the direction of Lp(a) effect seen, underscoring the strength of the conclusion that the prospective associations of Lp(a) with IHD are real.

There was marked heterogeneity in the extent of the relationship between Lp(a) and IHD between studies that was too great to be explained by chance alone. Our data suggest that this may be attributable in part to differences in sample storage temperature between studies. Although the inverse relationship between the Lp(a) case:control ratio and sample storage temperature was not statistically significant, it was large enough to suggest a trend and, moreover, was consistent with the results of formal storage studies. We have shown previously that sample storage may have a significant effect on Lp(a) concentration, with the extent differing according to temperature of storage (35). Kronenberg et al. (13) noted a proportional effect of sample storage on the results of Lp(a) measurement, in that greater loss of mass was noted among samples with low apo(a) molecular weight, even at -80 °C. Because there is an inverse association between apolipoprotein(a) size and Lp(a) mass (36), these data indicate that samples with higher Lp(a) concentrations had quantitatively lower recovery of Lp(a) concentration after storage; such an effect would tend to minimize observed differences in Lp(a) concentrations between cases and controls.

This sensitivity to storage temperature indicates that sample handling is a critical issue for studies using banked samples, and future studies should provide careful documentation of sample handling protocols. Regarding the present analysis, consideration of sample storage temperature effects suggests that the estimate we give for the Lp(a) case:control ratio is likely an underestimate of the actual relationship between Lp(a) and IHD.

At present there are no guidelines for the use of Lp(a) measurement in clinical practice, either as a screening test for IHD or to direct or monitor therapy in subjects with identified risk factors or disease. Even when a factor contributes to the development of a condition, this does not necessarily mean that its measurement is useful for screening. In the case of Lp(a), there is insufficient separation between concentrations from cases and controls to support the use of Lp(a) measurement as a screening test for IHD risk in the general population.

Although Lp(a) cannot be used as a screening test for IHD in the general population, its measurement may have a role in other clinical situations. For example, Lp(a) testing may be useful to monitor risk reduction efforts in subjects with IHD or high IHD risk. In addition, evidence from one study [40 subjects, 9 events ((37))] for interactions between Lp(a) and LDL in IHD risk has led to the suggestion that Lp(a) testing be used to identify individuals who might benefit from more aggressive LDL reduction therapy (38)(39).

Several elements must be considered in developing an objective strategy for clinical Lp(a) testing. First, Lp(a) assays must be standardized. Second, additional therapies must be developed to reduce Lp(a) concentrations. The presently available approach to reducing Lp(a) concentrations is essentially limited to the use of niacin (38), which is not universally tolerated. Third, intervention trials need to be performed to establish the benefit of Lp(a) reduction efforts. Finally, additional studies are needed to clarify the role of Lp(a) measurement in subjects undergoing therapy for other IHD risk factors.

	Acknowledgments

 
This work was supported by the Foundation for Blood Research Development Fund.

	Footnotes

 
Foundation for Blood Research, P.O. Box 190, Scarborough, ME 04070-0190.

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