HDL Apolipoprotein A-I and HDL Apolipoprotein A-II Concentrations in Male Company Employees in Westphalia Aged 40 Years and Older

J. Clin. Chem. Clin. Biochem.

Vol. 24, 1986, pp. 627-635

© 1986 Walter de Gruyter & Co.

Berlin · New York

HDL Apolipoprotein A-I and HDL Apolipoprotein A-II Concentrations in Male Company Employees in Westphalia Aged 40 Years and Older

By H. Schriewer, R Emke, H. Funke

Institut für Klinische Chemie und Laboratoriumsmedizin (Zentrallaboratorium) Medizinische Einrichtungen der Westfälischen Wilhelms-Universität Münster l Westfalen

H. Schulte

Institut für Arterioskleroseforschung an der Universität Münster, Münster l Westfalen and G. Assmann

Institutför Klinische Chemie und Laboratoriumsmedizin (Zentrallaboratorium) Medizinische Einrichtungen der Westfälischen Wilhelms-Universität Münster l Westfalen

(Received January 10, 1985/January 2/April 30, 1986)

Summary: The major structural components of high density lipoproteins were determined in the sera of 638 male employees aged 40 years and older. It was demonstrated that the HDL apolipoprotein A-I/HDL cholesteröl ratio äs well äs the HDL apolipoprotein A-II/HDL eholesterol ratio are similarly correlated to a cumulative score of established risk factors for atherosclerosis. Most important, however, is the finding that the correlation of these ratios to the risk factor rating of atherosclerosis is found in subgroups with normal or elevated HDL cholesteröl values. Furthermore, it is shown that the relative content of apolipoproteins - and A-II in individual HDL is partly dependent on the plasma concentration of HDL cholesteröl and triglycerides.

It is concluded that HDL composition may have an additional predictive significance for the development of atherosclerosis.

HDL^Apolipoprotein A^L· und HDL-Apolipoprotein A-II-Konzentrationen bei männlichen Betriebsangehörigen in Westfalen im Alter von 40 Jahren und darüber

Zusammenfassung: Im Serum von 638 männlichen Betriebsangehörigen im Alter von 40 Jahren und darüber wurden die Hauptstrukturkomponenten der "high density" Lipoproteine untersucht. Es wird gezeigt, daß sowohl das HOL-Applipoprotein A-I/HDL-Cholesterin-Verhältnis als auch das HDL-Apolipoprotein A-II/

HDL-Cholesterin-Verhältnis vergleichbar mit einem kumulativen Score von bekannten Risikofaktoren der Atherosklerose korreliert ist. Am bedeutsamsten ist die Beobachtung, daß die Korrelation zwischen diesen Quotienten und dem Risiko^Score in Untergruppen mit normalen und erhöhten HDL-Cholesterinwerten erhalten bleibt. Dariiberhiüaus wird gezeigt, daß der relative Anteil von Apolipoprotein A-I und Apolipopro- tein A-II in den HDL teilweise von der Konzentration von HDL-Cholesterin und Triglyceriden im Plasma abhängt.

Die Ergebnisse deuten darauf hin, daß der HDL-Komposition eine zusätzliche prädiktive Bedeutung für die Entwicklung der Atherosklerose zukommt.

J. Clin. Chem. Clin. Biochem. / Vol. 24,1986 / No. 9

Introduction

In recent epidemiological (1—4) and clinical studies (5 — 6) the analysis of high density lipoprotein cho- lesterol (HDL cholesterol) has been shown to be a risk indicator for coronary heart disease. In contrast to HDL cholesterol, the possible relationship of HDL apolipoproteins to the risk of coronary heart disease has not yet been thoroughly investigated. Several clinical studies have demonstrated low levels of apoli- poprotein A-I in subjects with coronary heart disease (7 — 9), while apolipoprotein A-II in patients with coronary heart disease has been found to be low (10, 11) or unchanged (6, 8). In contrast to these clinical studies there is a lack of the prospective epidemiologi- cal data needed to demonstrate the predictive potency of HDL apolipoproteins with respect to coronary heart disease. Recently, from initial results of our epidemiological study in Company employees in Westphalia, it was demonstrated that HDL apolipo- protein A-I correlates with several risk factors for coronary heart disease but fails to correlate with the risk factors triacylglycerol and relative body weight (12). To date, no comparable studies on HDL apoli- poprotein A-II are available. For a greater insight into the relationship between HDL apolipoproteins and the risk factors for coronary heart disease, we measured both HDL apolipoproteins A-I and A-II in 638 male Company employees in addition to HDL cholesterol. Since the incidence of coronary heart disease in women and in men under 40 years of age is very low, our study was limited to individuals aged 40 years and above.

Materials and Methods Sample material

Sera were obtained from male employees aged 40 years and over. All of these were participants in the "Prospective epidemi- ological study of Company employees in Westphalia" (13). Data given here are cross sectional. The proband's mean age was 49 ± 6 years, the maximum age being 64 years; observed body weight expressed s Broca index ranged from 69% to 151%

with a mean value of 106.6% ± 12.2%.

Analysis of HDL components

HDL components were analysed in the supernatant after preci- pitation of apolipoprotein B-containing lipoproteins with phos- photungstic acid/MgC!2 using the Boehringer Mannheim Test Combination (test no. 1442434) (14). HDL cholesterol was analysed enzymatically using the CHOD-PAP method (Boehringer Mannheim, test combination nol 237574) (14).

HDL phosphatidyl choline was determined with an enzyinatic colour test using the centrifugal analyser Cobas Bio (Hoffmann La R che) s described preViously (15).

Apolipoprotein A-I was determined turbidimetrically using the Cobas Bio analyser.

The incubation mixture contained:

— 300 μΐ phosphate-buffered polyethyleneglycol solution (Im- munochemical System Beckman)

- 20 μΐ d uted sample (dilution l: 160 with 9 g/l NaCl)

— 20 μΐ antibody solution (Behring antibody no. 103315 B was diluted with l : 2.5 with 9 g/l NaCl)

- 10μ1Η2Ο

As a blank, 300 μΐ phosphate-buffered polyethyleneglycol solu- tion was used, containing 20 μΐ diluted sample (dilution l: 160 with 9 g/l NaCl) and 10 ul H2O. After an incubation period at 25 °C changes in turbidity were recorded 30 times. For calibra- tion, a Standard solution of known concentration (Behring Apolipoprotein A Standard Serum Lot No. A 041206 K) was d uted l: 30, l: 60, l: 120, l: 240, and l : 480 with 9 g/l NaCL The parameter list for the Cobas Bio reads s follows:

1 unit

2 calculation factor 3 Standard l conc 3 Standard 2 conc 3 Standard 3 conc 3 Standard 4 conc 3 Standard 5 conc 6 limit

7 temperature ( °C) 8 type of analysis 9 wavelength (nm) 10 sample dilution (μΐ) 11 diluent volume (μΐ) 12 reagent volurne (μΐ) 13 incubation tinie (s) 14 start reagent volume (μΐ) 15 time of first reading (s) 16 time interval (s) 17 number of readings 18 blankingmode 19 printout mode

8 (mg/dl) 100023.1

46.292.4 184.8 369.6 25.00 3407.6

2020 30010 201.0 1030

ll

Using this turbidimetric method identical results were obtained when compared with data observed using kinetic nephelometry (16).

HDL apolipoprotein A-II was measured by turbidimetry using the Cobas Bio analyser s described in detail elsewhere (17).

LDL cholesterol

LDL cholesterol was calculated using the Friedewald method (18).

Total cholesterol, triacylglycerol, uric acid

Serum levels of cholesterol, triacylglycerol, glucose and uric acid were determined with the SMAC II Analyser (Techiucon GmbH, Bad V bel, FRG) s described elsewhere (13).

Statistics

For statistical calculations we used the statistical package for the social sciences (SPSS). To describe felationships to risk factors Spearman's correlation coefflcients were chosen since the risk factors were not always normally distributed, s proved by the Kolmogorov-Smirnow test. The correlations pf apolipo- proteins to the coronary risk score were calculated by KendalTs τ because of the high number of tied ranks. Differences in the distribution between subgroups were tested by the Kruskal- ' Wallis test. The level of significance was set at 0.05.

j. Clin. Chem. Clin. Biochem. / Vol. 24,1986 / No. 9

Results

Distribution of HDL apolipoprotein A-I and A-II

Figure l shows the HDL apolipoprotein A-I values measured in Company employees 40 years and older.

The parameters of distribution were:

mean: 1.444 g/l, S.D.: ± 0.222 g/l, median: 1.435 g/l, minimum 0.75 g/l, maximum 2.65 g/l, n = 617.

The corresponding values of apolipoprotein A-II are shown in figure 2:

mean: 0.427 g/l, S.D.: ± 0.073 g/l, median: 0.423 g/l, minimum: 0.248 g/l, maximum: 0.748 g/l, n « 638.

Correlation to cumulative risk factor rating To test the relationship between HDL cholesterol, HDL apolipoprotein A-I/HDL cholesterol ratio,

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HDL apolipoprotein A-I l g / i ]

Fig. 1. HDL apolipoprotein A-I values (g/l) in 616 normal male individuals 40 years and older. Epidemiological study of Company employees in Westphalia — cross sectional data. On the horizontal axis the upper bounds of the intervals are given.

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<0.31 0.320 0.345 0.370 0.395 0.420 0.445 0.470 0.495 0.520 0.545 >0.560 HDL apolipoprotein Α-Π [g/l]

Fig. 2. HDL apolipoprotein A-II values (g/l) in 638 normal male individuals 40 years and older. Epidemiological study of Company employees in Westphalia - cross sectional data. On the horizontal axis the upper bounds are given.

J. ςΐίη. Chem. Clin. Biochem. /Vol.24,1986/No. 9

HDL apolipoprotein A-II/HDL cholesterol ratio and risk factors, a cumulative risk factor rating was estab- lished for each subject. It was based on relative weight, diastolic blood pressure, cigarette smoking, cholesterol value and exercise. A score of 0, l or 2 was allocated for each of these measurements (tab.

1) and the sum of these individual scores was taken s the cumulative rating (19). The relation between each of the three parameters and increasing risk score was significant (p < 0.001 each). The distribution of the three parameters in the subgroups with a cumulative risk rating score of 0, l, 2—6 are demon- strated in figures 3, 4 and 5 where additionally the median values are indicated. The differences in the distributions between the subgroups are significant (Kruskal-Wallis test, p < 0.001 each). The relation- ship between the HDL apolipoprotein A-I/HDL cho- lesterol ratio and the cumulative risk rating score was comparable to the relationship of HDL cholesterol and the risk\score (tab. 2).

Tab. 1. Risk rating score sheet.

0 point l point 2 points Relative body weight <100 100-120 >120 (Broca Index, %)

Diastolic blood pressure < 90 90-110 >110 (mm Hg)

Cigarette smoking (no./day)

Cholesterol (mmol/) Exercise

non-smoker 1 — 2 0 > 20

< 6.72 6.72-7.75 > 7.75 very slightly inactive active active

An analysis of subgroups with low (< 0.91 mmol/1), normal (0.91 — 1.40 mmol/1) or elevated (> 1.40 mmol/1) HDL cholesterol values irevealed that the two ratios were related to the cumulative risk factor rating in subjects with normal or elevated HDL

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Fig. 3. HDL cholesterol in relation to eumulative risk factor rating. A '9' is printed if 9 or more men»have equal values.

r (Kendall) = -0.280 (p < 0.001)

J. Clin. Chem. Clin. Biochem. / Vol. 24,1986 / No. 9

Tab. 2. Correlation coefficients (Kendatfs τ) between the cor- onary risk score and HDL-cholesterol, HDL apolipo- protein A-I/HDL cholesterol, HDL apolipoprotein A- II/HDL cholesterol.

HDL apo-

! lipoprotein A-I/HDL cholesterol HDL cholesterol 0.092

; < 0.907 mmol/1 n = 112 HDL cholesterol 0.260***

; 0.907 -1.424 mmol/1 n = 369 HDL cholesterol 0.149*

> 1.424mmol/ n = 135 Total group 0.300***

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HDL cholesterol reflects an increased risk of develop- ing coronary heart disease.

HDL apolipoprotein A-I/HDL apolipopro- tein A-II ratio

The HDL apolipoprotein A-I/HDL apolipoprotein A-II ratio was positively correlated with HDL cho- lesterol (r = 0.194, p < 0.001) (tab. 3, fig. 6). Fur- thermore, in individuals with low HDL cholesterol values (< 0.907 mmol/1), a relatively low HDL-apoli- poprotein A-I/HDL apolipoprotein A-II ratio (3.23

± 0.47) was calculated. Individuais with high HDL cholesterol values (> 1.41 mmol/1) showed signifi- cantly higher HDL apolipoprotein A-I/HDL apolipo- protein A-II ratios (3.67 ± 0.52, p < 0.001). The HDL apolipoprotein A-I/HDL apolipoprotein A-II

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| men have equal values.

! r (Kendall) = -0.287 (p < 0.001)

J.Olin. Chem. Clin. Biochem. / Vol. 24,1986 / No. 9

Tab. 3. Correlation coefTicients (Spearman rank correlation) between the ratio, HDL apolipoprotein A-I/HDL apo- lipoprotein A-II, and cholesterol, triacylglycerol, HDL cholesterol and HDL phosphatidyl choline.

Cholesterol Triacylglycerol HDL cholesterol

HDL phosphatidyl choline

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ratio was negatively correlated with triacylglycerol (r:

-0.124, p < 0.001) (flg. 7, tab. 3). In individuals with triacylglycerol < 1.71 mmol/1, the HDL apoli- poprotein A-I/HDL apolipoprotein A-II ratio was found to be higher (3.51 ± 0.48) than in individuals with triacylglycerol ranging from 1.71 to 2.27 mmol/1 (3.33 ± 0.43) or hypertriacylglycerolaemic indivi- duals > 2.27 mmol/1 (3.33 ± 0.49). On the other band, there were no differences in the HDL apolipo- protein A-I/HDL apolipoprotein A-II ratio between hypertriacylglycerolaemic individuals and individuals with medium triacylglycerol values.

Discussion

In our present study we report only data on men 40 years and older, since this group obviously has a higher coronary risk than women or men under 40.

With respect to HDL cholesteibl and HDL apolipo- protein A-I, the data obtained from men 40 years and older did not differ significantly from data reported previously for Company employees from 25 to 64 years old (12). In addition to our previous study, HDL apolipoprotein A-II values were also measüred.

As previously reported (19) and äs again shown by the present results, HDL cholesterol has a negative correlation to the individual cumülative coronary risk based on the most frequent risk factors, obesity, hy- pertension, cigarette srnoking, cholesterol and exer- cise. In comparison with HDL cholesterol, the rela- tion of both ratios, HDL apolipoprotein A-I/HDL cholesterol and HDL apolipoprotein A-II/HDL chö- lesterol, to the individual cumülative risk did not differ. Furthermore, in individuals with normal or elevated HDL cholesterol values a higher coronary

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r (Kendall) = 0.300 (p < 0.001)

J. Cün. Chem. Clin. Biochem. / Vol. 24,1986 / No. 9

risk was associated with a higher ratio of HDL apoli- poprotein A-I/HDL cholesterol and HDL apolipo- protein A-II/HDL cholesterol. The reason for this observation may lie in possible changes in mass and composition of HDL subfractions caused by risk factors and in different associations of HDL subfrac- tions to coronary risk. It is known that changes in plasma HDL level mainly affect HDL2 (20) and that an inverse correlation exists between HDL and VLDL in plasma (21). Furthermore, it has been shown that a less dense HDL2 subfraction (relative high lipid/apolipoprotein ratio) is epidemiologically associated with reduced coronary heart disease, while a more dense HDL³ subfraction (relatively low lipid/

apolipoprotein ratio) is thought to be unrelated to such disease (22, 23). Nevertheless, recent studies have shown that HDL in individuals with hypertri- acylglycerolaemia mainly consist of HDL3, which are enriched with apolipoproteins and triglycerides and which are depleted of cholesterol (24). Furthermore, it has been reported that alcohol consumption, which is known to be associated with high HDL cholesterol

(25 — 27) and frequently with hypertriacylglycerol- aemia (28, 29), mainly resulted in an enhanced level of HDL3 mass without affecting HDL2 mass (30).

It has been shown that the apolipoprotein A-I/apoli- poprotein A-II ratio in HDL/2 is higher than that in HDL3 (31, 32). Therefore, in individuals with heigh HDL cholesterol levels (which are associated with lower triacylglycerol) and a similarly high apolipo- protein A-I/apolipoprotein A-II ratio, a higher HDL2/HDL3 ratio may exist in comparison to indivi- duals with lower HDL cholesterol levels (which are associated with higher triacylglycerol) and a similarly low apolipoprotein A-I/apolipoprotein A-II ratio.

However, it is of interest to note that the HDL lipoprotein composition in our study did not differ between individuals with moderate hyperlipoprotein- aemia and individuals with obviously enhanced lipid levels. Possibly, in hypertriacylglycerolaemics, the HDL apolipoprotein A-I/apolipoprotein A-II ratio may additionally be a reflection of the change in apolipoprotein composition in HDL particles in dif- ferent density classes.

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r (Spearmari) = 0.194 (p < 0.01)

J. Olin. Chem. Clin. Bicwhem. / Vol. 24,1986 / No. 9

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275 — 286. Professor Dr. H. Schriewer Institut für Klinische Chemie und Laboratoriumsmedizin Medizinische Einrichtungen der Westf. Wilhelms-Universität Albert-Schweitzer-Straße 33 D-4400 Münster

J. CHn. Chem. Clin. Biochem. / Vol. 24,1986 / No. 9

ORIGINAL IKA

pitzeriqualität aus dem Schwarzwald

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D. M. Goldberg · M. Werner

(Editors)

Selected Topics in Clinical Enzyrnoßogy

Proceedings (selected) of the Third Inter- national Congress pf Clinical Enzymology Salzburg, Austria, September 6-9,1981 1983.17 cm 24 cm. XVIII, 362 piages. With numerous illustrations. Hardcover. DM 160,-;

approx. US-$72.75 ISBN 311 009688 9

This book contains 27 contributipns provid- ing comprehensive cover of the applicatiqn pf enzymes in four important aspects of Clin- ical Enzymology:

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By means of carefully selected reviews and original ärticles, the reader is brought up to date with the tatest advances in these topics.

An Authof Index and a Comprehensive Subject Index are included.

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G Walter de Gruyter · Berlin · New York

Verlag Walter de Gruyter & Co., Genthiner Str. 13, D-1000 Berlin 30, Tel.: (030) 26005-0, Telex 184027 Walter de Gruyter, Inc., 200 Saw Mill River Road, Hawthorne, N.Y. 10532, Tel.: (914) 747-0110, Telex 646677