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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1001-1008

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1001-1008.)
© 1995 American Heart Association, Inc.

Articles

Apo(a) Phenotypes and Lp(a) Concentrations in Offspring of Men With and Without Myocardial Infarction

The EARS Study

Ib Christian Klausen; Ulrike Beisiegel; Hans-Jürgen Menzel; Maryvonne Rosseneu; Viviane Nicaud; Ole Faergeman; on behalf of the EARS Group

From the EARS Group (see "Appendix" for list of study participants).


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
Abstract In the European Atherosclerosis Research Study, genetic and environmental markers of risk of premature coronary heart disease were compared in offspring of men with and without myocardial infarction before the age of 55 years. Cases were 682 students with a paternal history of myocardial infarction, and control subjects were 1312 students without such a history. The students were enrolled in 14 universities in five European regions (Finland, Great Britain, and northern, middle, and southern Europe). Lipoprotein(a) [Lp(a)] concentrations were skewed towards lower concentrations in both cases (median, 7.3 mg/dL; 95% confidence interval, 6.3 to 8.1 mg/dL) and control subjects (median, 6.6 mg/dL; 95% confidence interval, 6.1 to 7.2 mg/dL) (P=.37). Significantly more northern European male cases than control subjects had Lp(a) levels exceeding 30 mg/dL (P=.040), but this did not pertain to females (P=.29), and overall, there was no difference between cases (16.5%) and control subjects (15.5%) in the frequency of Lp(a) concentrations above 30 mg/dL (P=.63). As expected, there was a significant (P<.01) inverse relationship between apo(a) molecular size and Lp(a) concentration. In Great Britain there was a significant difference in phenotype distribution between cases and control subjects (P=.035), due mainly to a high frequency of the apo(a) S2 isoform in cases. A similar but statistically insignificant tendency was seen in northern Europeans. In the three other regions, however, the distribution of apo(a) phenotypes among cases and controls was similar, and in the study population overall, the distribution of apo(a) phenotypes did not differ significantly (P=.74) between cases and control subjects.


Key Words: lipoprotein(a) • apolipoprotein(a) • lipoproteins


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
Lp(a) is a subspecies of LDL in which a glycoprotein, apo(a), is attached to the protein component of LDL, apoB.1 Plasma concentrations of Lp(a) are largely controlled by the apo(a) gene locus on chromosome 6.2 3 The size of the gene is directly correlated to the size of the allelic gene product, apo(a), and inversely correlated to plasma concentrations of Lp(a).2 3 4

Several5 6 7 8 but not all9 10 11 12 13 14 case-control studies have shown that high Lp(a) levels are associated with atherosclerotic disease, including myocardial infarction (MI). Most of these studies were retrospective,5 11 12 13 and it is a source of possible bias that the disease itself could affect Lp(a) concentrations.15 16 Because atheroma develops very slowly, a similar bias could in fact also apply to prospective studies.16

A way to circumvent this problem is to see whether the frequency of genetically determined apo(a) phenotypes is increased in patients with atherosclerotic disease. Small apo(a) isoforms (B, S1, and S2) were indeed significantly associated with coronary heart disease (CHD) in a study of six different populations16 and with intermittent claudication in Swedish men.17 Another way to exploit the strong genetic influence of the Lp(a) polymorphism on plasma Lp(a) concentrations18 in studies concerning Lp(a) and atherosclerotic disease is to determine whether persons closely related to patients with atherosclerotic disease have higher plasma Lp(a) concentrations.19 20 21 22 23

The incidence of CHD varies considerably between European countries. For example, age-standardized CHD mortality rates are three to four times higher in Scotland and Finland than in the Mediterranean countries.24 The European Atherosclerosis Research Study (EARS) is a study of genetic and environmental indicators of risk of CHD in male and female European university students with and without a paternal history of myocardial infarction before the age of 55 years.25

In this article we present the Lp(a) results of EARS. Measurements made in the control group, unbiased by presence of the disease in the family, enabled us to study differences in apo(a) frequencies and Lp(a) concentrations between populations with different rates of CHD mortality. Moreover, we studied the possible associations of apo(a) frequencies and Lp(a) concentrations with paternal history of early MI.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
Subjects
The design of EARS has been described elsewhere.25 In brief, students were recruited and studied between October 1990 and February 1991. They attended universities in 14 European cities (Fig 1Down), which for purposes of analysis were grouped a priori into five regions: Finland (Oulu and Helsinki), Great Britain (Glasgow, Scotland and Bristol, England), northern Europe (Göteborg, Sweden; Aarhus, Denmark; and Hamburg, Germany), middle Europe (Ghent, Belgium; Zurich, Switzerland; and Innsbruck, Austria), and southern Europe (Bordeaux, France; Barcelona and Reus, Spain; and Naples, Italy). Criteria for grouping were known regional differences in CHD mortality rates,24 geography, and language, because interpopulation genetic differences roughly follow boundaries between major language groups. The students were between 18 and 26 years of age, and students whose fathers had a documented MI before the age of 55 were defined as cases (n=682). Each case was matched by sex and age to two students without a family history of CHD (control subjects; n=1312). The mean age of control subjects' fathers was slightly but significantly higher than the mean age of cases' fathers at MI (53.3±0.2 and 52.6±0.3 years, respectively; P<.01). The diagnosis of paternal nonfatal MI was based on criteria of the World Health Organization, and to ascertain fatal MI in the father we used a system involving five diagnostic subclasses.25



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  		Figure 1. Map shows the locations of the 14 universities participating in the European Atherosclerosis Research Study.

Venous blood was collected after an overnight fast, and frozen serum samples were shipped to University Hospital St. Jan, Brugge, Belgium, for Lp(a) measurements. We did not have access to serum from 85 students, reducing the number of subjects for analysis to 1909 (645 cases and 1264 control subjects). Apo(a) phenotyping was performed in three laboratories (Innsbruck, Hamburg, and Aarhus), and one third of the samples from each recruitment center were shipped (frozen)25 to each of the three laboratories. Apo(a) phenotypes were determined in 646 cases and 1259 control subjects (samples from 89 students were missing). Data were processed and analyzed at INSERM U.258 in Paris, France.

Lp(a) Determination
Lp(a) was quantified with a sandwich-type enzyme-linked immunosorbent assay (ELISA)26 by use of a combination of a monoclonal antibody against apo(a) for coating and a stable polyclonal anti-apoB–peroxidase conjugate for detection. The conjugate was prepared from high-affinity anti-apoB immunoglobulins by use of the periodate coupling procedure. After immunization of BALB/c mice with Lp(a), we obtained 14 stable clones that were tested for specificity against LDL, plasminogen, and apo(a). We selected the 1D1 clone, an IgG1k, with high affinity and specificity for apo(a). For the ELISA, polystyrene microtiter plates were coated with the purified monoclonal antibody 1D1 at 4 µg per milliliter of coating buffer. Plates were blocked with the assay buffer, a sodium phosphate buffer (0.05 mmol/L, pH 7.4, plus 0.15 mol/L NaCl and 1 g/L casein), for 1 hour at 23°C. Between incubations, we washed the plates with assay buffer containing 0.5 mL/L added Tween-20 (Bio-Rad Labs).

For the sandwich ELISA for Lp(a), plasma samples and conjugate were diluted 2000- and 6000-fold, respectively, with the buffer used for blocking. The samples were incubated with either the immobilized antibody or the conjugate for 2 hours at 37°C. The peroxidase activity, with o-phenylenediamine as substrate, was measured by reading of the absorbance at 490 nm. Calibration curves were prepared from appropriate dilutions of purified Lp(a). Intra-assay and interassay coefficients of variation were determined at low (50 mg/L), medium (200 mg/L), or high (750 mg/L) Lp(a) concentrations. The mean coefficients of variation obtained were <3% (intra-assay) and 5% (interassay). The assay was calibrated with a highly purified Lp(a) fraction isolated from pooled human plasma. The protein content of this primary standard was determined by a Folin-Lowry assay in the presence of SDS. Lp(a) protein was converted to lipoprotein mass with the assumption that the average protein content of Lp(a) is 35%. A set of serum samples of different Lp(a) concentrations (30 to 800 mg/L) was used for internal quality control and stored in portions at -20°C for 2 years. No effect of storage was observed, provided that the samples were not thawed more than once. All Lp(a) determinations of the case-control samples were performed on frozen specimens.

Apo(a) Phenotyping
Apo(a) phenotypes were determined by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting by a method slightly modified from that described by Utermann et al.18 The samples were prepared by mixing 4 µL of serum (null phenotypes and single banded phenotypes were redetermined with 6 to 8 µL) with 50 µL of a 0.02 mol/L ethylmorpholine buffer containing 50 g/L SDS (BDH Chemicals UK). 2-Mercaptoethanol (4 µL) and a 15 g/L bromophenol blue solution in glycerol (2 µL) were added, and the samples were boiled for 10 minutes. Aliquots of 5 µL (Innsbruck) or 25 µL (Hamburg and Aarhus) were then subjected to SDS-PAGE in a discontinuous buffer and gel system27 with a stacking gel containing 3.6% polyacrylamide and a resolving gel of 5.2% polyacrylamide. Acrylamide and N,N'-methylene-bis-acrylamide were purchased from LKB, and the electrophoresis equipment was either the Desaphor va. from Desaga (Hamburg and Aarhus) or the Minigel Twin from Biometra (Innsbruck). In Innsbruck, proteins were transferred to nitrocellulose filters (BA85, 0.45 µm, Schleicher and Scheull) by the method described by Towbin et al28 with the Trans blot cell (Bio-Rad). Antigens were visualized on the nitrocellulose filters by a double-antibody procedure. The first antibody was a monoclonal anti-Lp(a) raised in mice,29 and the second was a rabbit anti-mouse peroxidase conjugate (DAKO-PATTS).

The various apo(a) isoforms were designated according to their relative electrophoretic mobility on SDS-PAGE compared with apoB-100, with the terminology proposed by Utermann et al.4 F denotes a fast-migrating isoprotein smaller than apoB-100, and S1, S2, S3, and S4 denote larger isoproteins with progressively lower mobility than apoB-100. B is a band with the same mobility as apoB-100. Null type (0) designates blots showing no bands at all. As references, samples from heterozygotes with phenotypes S1S2, BS4, and FS3 were obtained from a study of healthy Caucasian Danes30 and run alternately in every fourth lane. Sample isoforms were classified by comparison with the closest reference. Classification was done without knowledge of whether the sample was from a case or a control subject.

Other studies have shown that some of the 22 potential phenotypes are infrequent.30 To avoid empty "cells" in the statistical comparisons of the apo(a) frequencies, we combined a priori the apo(a) phenotypes into four groups according to molecular weight (Table 1Down). To compare our results with those of Sandholzer et al,16 we further divided the phenotypes into two classes. Class A comprised the subjects with at least one of the isoforms F, B, S1, and S2, and class B comprised the subjects with the isoforms S3, S4, and 0 (Table 1Down).


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  		Table 1. Frequencies of Apo(a) Phenotypes in the Study Population (n=1905)

Statistical Methods
Lp(a) concentrations in control populations and in cases and control subjects were compared by the Kolmogorov-Smirnov test and by one-way ANOVA after logarithmic transformation of data.31 The {chi}2 test was used to compare distributions on apo(a) groups among cases and controls and among populations and for comparison of cases and controls with Lp(a) levels above 30 mg/dL. The Kruskal-Wallis test was used for comparison of Lp(a) concentrations between phenotype groups. As a measure of association between apo(a) class and case or control status, odds ratios with 95% confidence intervals were calculated from 2x2 tables. The Mantel-Haenszel test statistic was calculated from the stratified 2x2 tables.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowAppendix 1
 down arrowReferences
 
In the study population overall, median Lp(a) concentrations in men (7.0 mg/dL; 95% confidence interval [CI], 6.6 to 8.1 mg/dL) and women (6.6 mg/dL; 95% CI, 6.1 to 7.4 mg/dL) did not differ significantly, but women taking oral contraceptives had significantly (P=.012) lower median Lp(a) concentrations (5.9 mg/dL; 95% CI, 4.8 to 6.7 mg/dL) than women not taking them (7.3 mg/dL; 95% CI, 6.5 to 8.3 mg/dL). The percentage of women using oral contraceptives did not differ significantly between the case and control groups (38.7% and 35.5%, respectively).

Lp(a) Concentrations and Apo(a) Phenotypes in Control Subjects by Region
Lp(a) concentrations differed significantly between regions (P=.01). This difference was not significant in men analyzed separately (P=.23), but it was significant in women (P=.01) and in the subgroup of women not taking oral contraceptives (P=.03). In men, the median Lp(a) concentration was lowest in Finland (5.2 mg/dL; 95% CI, 3.9 to 8.5 mg/dL), highest in Great Britain (7.6 mg/dL; 95% CI, 4.6 to 15.0 mg/dL), and practically identical in the three other regions. In women, Lp(a) concentrations were also lowest in Finns (4.2 mg/dL; 95% CI, 3.5 to 5.9 mg/dL), but they were highest in southern Europeans (8.2 mg/dL; 95% CI, 6.6 to 9.9 mg/dL). The inverse relationship between apo(a) molecular weight and Lp(a) concentration was statistically significant in all five regions (P<.01) (data not shown). This relationship is also apparent after grouping of phenotypes (Table 2Down and Fig 2Down). In general, the null and the large molecular weight isoforms (phenotype group IV) occurred more frequently than the small molecular weight isoforms (phenotype group I), and with one exception (northern Europeans), the rank order of phenotype group frequency was IV>III>II>I (Table 3Down).


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  		Table 2. Median Concentrations of Lipoprotein(a) According to Apo(a) Phenotype Group, Paternal History of Myocardial Infarction, and Region



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  		Figure 2. Graphs show comparisons of lipoprotein(a) Lp(a) concentrations in control subjects and cases within the same phenotype groups from five regions of Europe.


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  		Table 3. Distributions of Phenotype Groups According to Region and Paternal History of Myocardial Infarction

Because Lp(a) concentrations are largely determined by polymorphisms in the apo(a) gene locus, here expressed as apo(a) phenotypes, we investigated whether regional differences in Lp(a) concentrations in control subjects were functions of the phenotypes. Multiple pairwise comparisons of regional apo(a) phenotype frequencies indicated that there were two major geographical areas within which phenotype frequencies were similar and between which phenotype frequencies differed significantly. One of these regions was defined by the control subjects in the Finnish, middle European, and southern European universities, and the other was defined by the control subjects in the universities in Great Britain and northern Europe. After adjustment for regional differences in phenotype frequencies, the overall regional difference in Lp(a) concentration was no longer statistically significant (P=.54).

Case-Control Study
In both cases and control subjects, the distribution of Lp(a) concentration was skewed towards lower concentrations (Fig 3Down). Although the median Lp(a) concentration was somewhat higher in cases (7.3 mg/dL; 95% CI, 6.3 to 8.1 mg/dL) than in control subjects (6.6 mg/dL; 95% CI, 6.1 to 7.2 mg/dL), this difference was not statistically significant. The similarity between the distributions of Lp(a) concentration in cases and control subjects by region and overall is apparent when they are depicted as cumulative frequency curves (Fig 3Down).



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  		Figure 3. Cumulative frequency distributions show Lp(a) concentrations in subjects with (cases) and without (control subjects) a paternal history of myocardial infarction before the age of 55 years. Data are shown from five regions of Europe and for the study population as a whole. Median concentrations of Lp(a) (in mg/dL) with 95% confidence intervals for cases and control subjects are shown on each graph. For statistical comparisons, see text.

Neither in men (P=.28) nor in women (P=.98) did Lp(a) concentrations differ significantly between cases and control subjects (data not shown). In northern Europe only, slightly higher Lp(a) concentrations in male cases than in male control subjects were borderline significant (P=.052). Moreover, significantly more northern European male cases than male control subjects had Lp(a) concentrations exceeding 30 mg/dL (P=.040). This did not pertain to northern European women (P=.29), however, and overall, Lp(a) concentrations exceeding 30 mg/dL were found in 16.5% of cases and in 15.5% of control subjects (P=.63).

In the total study population, the distribution of cases and control subjects according to the four groups of apo(a) phenotypes did not differ significantly (P=.74) (Table 3Up). This also pertained to each region with the exception of Great Britain, where there was a significant difference (P=.035) due to a higher frequency of cases in group II and a higher frequency of control subjects in group I (Table 3Up). When groups I and II are considered together (class A), as in the classification system proposed by Sandholzer et al,16 differences in phenotype classes between cases and control subjects were not significant (Table 3Up). There was a tendency, however, for cases in Great Britain and northern Europe to belong to class A. Odds ratios with CIs are given in Table 3Up. The Mantel-Haenszel test statistic was calculated from the stratified 2x2 tables (class A versus class B [group III plus group IV]) but, again, the difference was not statistically significant (Mantel-Haenszel test statistic=0.53, P=.47). Within the same phenotype groups, Lp(a) tended to be higher in cases than in control subjects in Finland and Great Britain, but these differences were not significant (Table 2Up).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowAppendix 1
 down arrowReferences
 
When we embarked on the EARS, we had expected that Lp(a) concentrations and Lp(a) phenotypes would be clearly different in subjects with and without a paternal history of CHD. That was not the case, and we have considered whether methodological problems could explain a negative result. Classification of apo(a) phenotypes could be subject to observer bias, but the EARS investigators who classified phenotypes had no way of knowing whether samples were from cases or control subjects. Moreover, salient results of the EARS are entirely as expected. First, the skewness of the Lp(a) concentration distribution in our study was very similar to that found in earlier studies of Caucasians.30 32 Second, we found exactly the relationship between apo(a) size polymorphism and plasma Lp(a) concentrations that would be expected on the basis of results of other studies.4 18 30 32 We therefore do not believe that the similarity of Lp(a) findings in cases and control subjects is a spurious result. It should be stressed, however, that the statistical power of offspring studies is smaller than that of case-control studies, because disease-related genes are not necessarily transmitted to offspring.

In contrast, there were real, albeit slight, regional differences in Lp(a) findings in control subjects. The relationship between apo(a) phenotype group and Lp(a) levels was the same in all regions studied (Fig 2Up). Regional differences in Lp(a) concentrations between both case group and control group subjects, therefore, were consistent with differences in the distribution of apo(a) phenotypes. Moreover, because Lp(a) concentrations varied very little within phenotype groups, it is likely that regional differences in Lp(a) concentrations were mainly due to differences in distribution of apo(a) alleles and that the influence of other factors, genetic or environmental, was minor.

Multiple comparisons of regional phenotype groups suggested two major geographical regions within which Lp(a) phenotypes are grossly similar and between which they are somewhat different. One region comprises Finland, where CHD mortality is high (3.86/1000 per year), but also middle and southern Europe, where CHD mortality rates are low (1.81/1000 and 1.20/1000 per year, respectively). The other region comprises two populations with high CHD rates, Great Britain (3.57/1000 per year) and northern Europe (2.93/1000 per year).

In some studies, Lp(a) data apparently do contribute to an understanding of regional differences in CHD rates. For example, Parra et al33 found lower Lp(a) concentrations in a French low-risk population than in a population at higher risk (Northern Ireland), and in Greenland Eskimos, who also are at low risk of CHD, Klausen et al30 found a very low frequency of low–molecular weight apo(a) isoforms. In contrast, the Congolese34 and the Sudanese32 have high mean levels of Lp(a), but like American blacks, they are probably at low risk of CHD.

Whether or not genetically determined plasma concentrations of Lp(a) cause disease may therefore depend on interaction of Lp(a) with environmental or other genetic factors. In a coronary angiographic study, Armstrong et al35 provided evidence that the atherogenicity of Lp(a) depended on ambient concentrations of LDL: Lp(a) was associated with angiographic changes only if LDL concentrations were high. Moreover, Lawn et al36 showed that transgenic mice expressing apo(a) developed more lipid-staining lesions in the aorta than did control littermates when both groups were fed an atherogenic diet. Transgenic mice maintained on a low-fat diet did not develop lesions.

LDL and other factors may of course vary substantially between populations as a function of environment and genetics. Genes in close linkage to the apo(a) locus could modulate the effect of Lp(a) on CHD, and if the degree of disequilibrium between apo(a) and a putative second gene differs between populations, then apo(a) would be associated with CHD in some populations but not in others.

Previous studies with designs similar to that of our study suggest that, at least in Caucasians, a family history of CHD is related to high Lp(a) concentrations in offspring.19 20 21 22 23 In an early study by Berg et al,19 Lp(a) was more frequently detected in the plasma of north Swedish males with a family history of CHD than in men without a family history of disease. More recently, studies have shown that children of patients with CHD have higher levels of Lp(a)20 21 22 23 or a higher frequency of low–molecular weight apo(a) phenotypes23 than children of unaffected parents. There was a racial difference, however, because Lp(a) indicated parental risk of MI in Caucasians but not in blacks.22 Compared with the EARS, these studies were small, and they were each performed in a single geographical region. When each of the regions in the present study was studied separately, significantly different Lp(a) findings in cases and control subjects were made in only two of them.

In a case-control study of Sandholzer et al,16 the small apo(a) isoforms (B, S1, and S2) were related to CHD in three of six populations. The results were not significant in the Israeli population, the largest of the populations studied. The absence of an association between Lp(a) concentrations and paternal history of CHD in the Finnish students of our study agrees with results of the Helsinki Heart Study, in which Lp(a) was not a predictor of future coronary events.14 In another Finnish study, Nieminen et al10 similarly found no relationship between median Lp(a) and angiographically verified CHD. Other studies suggesting no association of Lp(a) to CHD have been reported from middle Europe (Belgium),13 the United States,9 and southern Europe (Italy).12 Thus, it is possible that the importance of Lp(a) as a risk factor for cardiovascular disease differs between races and between populations within the same race.

There is increasing experimental and clinical evidence that Lp(a) is atherogenic. Lp(a) can be found in atheromatous plaques as well as in coronary bypass grafts,37 38 and the affinity of Lp(a) for glycosaminoglycans, fibrin, and fibronectin is higher than that of LDL.39 40 Moreover, because of the structural similarities between Lp(a) and plasminogen,41 Miles et al42 suggested that Lp(a) could play a role in thrombogenesis, and they found that Lp(a) could bind to and displace plasminogen from plasminogen receptors on peripheral blood cells and vascular endothelial cells. The inference is that Lp(a) could prevent formation of plasmin and thereby thrombolysis. At this time, however, we cannot rule out the possibility that the homology between apo(a) and plasminogen is functionally unimportant, and there is no in vivo evidence of a thrombotic effect of Lp(a). In two studies, Lp(a) concentrations were not related to the risk of venous thrombosis.43 44

Animal experiments and clinical trials will be needed to test the hypothesis that Lp(a) causes atherosclerosis and ischemic heart disease. At present, however, no agent that selectively lowers Lp(a) is available to extensively test the proposal that reduction of Lp(a) also lowers the risk of disease in humans.


*    Footnotes
 
Reprint requests to Ole Faergeman, Department of Medicine and Cardiology A, Aarhus Amtssygehus University Hospital, Tage Hansensgade 2, DK-8000 Aarhus C, Denmark.


*    Appendix 1
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *Appendix 1
down arrowReferences
 
EARS Project Leader, J. Shepherd, Glasgow, UK.

EARS Project Management Group: F. Cambien, Paris, France; G. De Backer, Ghent, Belgium; M.-M. Galteau, Nancy, France; D. St. J. O'Reilly, Glasgow, UK; M. Rosseneu, Brugge, Belgium; and L. Wilhelmsen, Göteborg, Sweden.

EC COMAC–Epidemiology Liaison Officer, T. Sörensen, Copenhagen, Denmark.

The EARS Group Investigators and the collaborating centers:

Austria: H.J. Menzel, C. Sandholzer, C. Duba, and H.G. Kraft, Institute for Medical Biology and Genetics, University of Innsbruck (recruitment center and laboratory).

Belgium: G. De Backer, S. De Henauw, D. De Bacquer, and A. Bael, Department of Hygiene and Social Medicine, State University of Ghent (recruitment center).

Belgium: M. Rosseneu and N. Vinaimont, Department of Clinical Chemistry, University Hospital St. Jan, Brugge (laboratory).

Denmark: O. Faergeman, C. Gerdes, L.U. Gerdes, and I.C. Klausen, Medical Department A, Aarhus Amtssygehus University Hospital, Aarhus (recruitment center and laboratory).

Finland: C. Ehnholm, National Public Health Institute (recruitment center and laboratory); R. Elovaino, P. Palomaa, and J. Peräsalo, The Finnish Student Health Service, Helsinki; and A. Kesaniemi, Department of Internal Medicine, University of Oulu (recruitment center).

France: F. Cambien, L. Tiret, R. Agher, V. Nicaud, and R. Rakotovao, INSERM U.258, Unité de Recherche d'Epidémiologie Cardiovasculaire, Hôpital Broussais (EARS data center and recruitment center), and L. Bara, Laboratories de Thrombose Expérimentale (laboratory), Paris; M.-M. Galteau and S.M. Visvikis, Centre de Médecine Préventive, Nancy (EARS central laboratory); J.C. Fruchart, J.M. Bard, and P. Lebel, Service de Recherche sur les Lipoproteines et l'Athérosclérose, INSERM U.325, Institut Pasteur, Lille (laboratory); and C. Bady, J. Beylot, A. Lindoulsi, and L. Tiret, UFR de Santé Publique, Bordeaux (recruitment center).

Germany: U. Beisiegel, A. Jorge, and M. Papanicolaou, I. Medizinische Klinik, Universitätskrankenhaus Eppendorf, Hamburg (recruitment center and laboratory).

Italy: E. Farinaro, M. Mancini, and S. Varrone, Institute of Internal Medicine and Metabolic Disease, University of Naples (recruitment center).

The Netherlands: L.M. Havekes and P. de Kniff, IVVO-TNO Health Research, Gaubius Institute, Leiden (laboratory).

Spain: S. Sans and T. Puig, Programma CRONICAT, Hospital Sant Pau, Barcelona (recruitment center), and P.R. Turner, M. Masana, A.E. La Ville, and J. Balanya, Unitat Recerca Lipids, Universitat Barcelona, Reus (recruitment center and laboratory).

Sweden: L. Wilhelmsen, I. Wallin, and S. Johansson, Department of Medicine, Ostra Hospital, University of Göteborg (recruitment center).

Switzerland: F. Gutzwiller, B. Marti, M. Knobloch, and P. Anliker, Institute of Social and Preventive Medicine, University of Zurich (recruitment center).

United Kingdom: D. Stansbie, H. Denton, and S. Plumridge, Department of Chemical Pathology, Royal Infirmary, Bristol (recruitment center); J. Shepherd, D. St. J. O'Reilly, G.W. Tait, and G.M. Hamilton, Institute of Biochemistry, Royal Infirmary, Glasgow (recruitment center and laboratory); and S. Humphries, P. Talmud, and S. Ye, University College London School of Medicine, London (laboratory).

Received July 6, 1994; accepted April 26, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 up arrowAppendix 1
 *References
 

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