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VOLUME 78. AUGUST 1986. NUMBER 2

Pediatrics

Serum

Apolipoproteins

A-I and

B in 2,854

Children

From

a Biracial

Community:

Bogalusa

Heart

Study

Sathanur R. Srinivasan, PhD, David

S. Freedman,

PhD,

Chakravarthi Sharma, PhD, Larry S. Webber, PhD, and

Gerald

S. Berenson,

MD

From the Departments of Medicine, Biochemistry, Public Health and Preventive Medicine, and Biometry and Genetics, Louisiana State University Medical Center, New Orleans

ABSTRACT. Serum apolipoprotein A-I (apo A-I) and

apolipoprotein B (apo B) profiles were examined in 2,854

children, 5 to 17 years of age, from a total biracial

community. Black boys had higher apo A-I levels than white boys (P < .001), whereas girls showed no such

race-related difference. Black-white difference in apo A-I

per-sisted among boys with similar triglyceride levels

pro-vided that triglyceride levels were high. The ratio of

high-density lipoprotein cholesterol (HDL-C)/apo A-I was higher in black than in white children, irrespective of sex

(P < .001). Only black children showed sex-related

dif-ferences for apo A-I (boys > girls, P < .05). Sex-related differences were seen in white children for HDL-C/apo

A-I ratio (boys > girls, P < .001) and in children of both

races for apoB (girls > boys, P < .01). Age-related changes

were more apparent for apo A-I and HDL-C/apo A-I

ratio than for apo B. A progressive decrease in apo A-I

was noted during sexual maturation only in white boys.

The magnitude of inverse association of apo B to

HDL-C was less strong in black children (P < .01). Although apo A-I was inversely correlated with very low-density lipoprotein cholesterol and triglycerides in white

chil-dren, no association was noted in black children. These

findings are indicative of intrinsic metabolic differences

among the race-sex groups, resulting in variability in

lipoprotein composition and levels and atherogenic

po-tential. Pediatrics 1986;78: 189-200; apolipoprotein A-I, apolipoprotein B.

Received for publication May 28, 1985; accepted Nov 21, 1985. Reprint requests to (G.S.B.) Department of Medicine, LSU Medical Center, 1542 Tulane Aye, New Orleans, LA 70112.

PEDIATRICS (ISSN 0031 4005). Copyright © 1986 by the

American Academy of Pediatrics.

The pathologic precursors of coronary heart

dis-ease are now recognized as originating in

child-hood.’3 Serum lipoproteins are considered

impor-tant risk factor variables in this regard, with

low-density lipoproteins (LDL) and high-density

lipo-proteins (HDL) showing positive and inverse risk

associations, respectively.47 Consequently, there

has been a surge of interest in studying the

evolu-tion of serum lipoprotein profiles in children.

Recently, serum lipid and lipoprotein

distribu-tions in US children from major population-based

studies have been reported.81’ Of these, the

Boga-lusa Heart Study provides lipoprotein profiles of a

biracial (black-white) pediatric population. Our

studies show that the most dramatic changes in

serum lipids and lipoproteins occur during the first

year of life, with the mean level of total cholesterol

essentially approaching the young adult level by 1

to 2 years of age.12”3 Age- and sex-related

differ-ences in lipoproteins differ markedly from adult

patterns. Lipoprotein transitions occur during

sex-ual maturation so that adult patterns of elevated

levels ofboth very low-density lipoproteins (VLDL)

and LDL and decreased levels of HDL in males v

females are reached.14”5 In addition, consistent

race-related differences exist in children for VLDL

(whites > blacks) and

HDL

(blacks

> whites).9”6

The above lipoprotein changes are measured in

(2)

and HDL-C), one of several components of lipopro-teins.

Serum lipid classes are bound in a spectrum of

proteins called apolipoproteins, which are an

inte-gral part of lipid transport. Among the known

apo-lipoproteins (apo), B and A-I are of particular

in-terest. Apo B is the predominant protein

constitu-ent of VLDL and LDL and serves as the principal

carrier of lipids to peripheral tissues.’7 On the other

hand, apo A-I is found as the major apolipoprotein

of HDL particles and functions as an activator of

lecithin-cholesterol acyltransferase, a key enzyme

in the reverse transport of cholesterol from the

peripheral tissues.’8”9

Studies in adults suggest that apolipoproteins

may serve as better predictors of coronary heart

disease than lipoprotein cholesterol.20’2’ To date,

there are only a few studies describing

apolipopro-tein levels in the general adult population.2224 The

present study describes the apo A-I and apo B

profiles in 5- to 17-year-old children from a biracial

community.

MATERIALS

AND

METHODS

Population

In 1981 to 1982, 3,314 five- to 17-year-old

school-children residing in Bogalusa, LA, were examined,

representing 80.2% of all eligible individuals. With

this participation rate it is reasonable to conclude

that the sample was representative of the target

population. Observations from a substudy of 761

nonparticipants revealed that less than 6% of older

nonparticipants refused because of “medical

prob-lems,” and more than 30% of these individuals

expressed outright refusal without giving specific

reasons.25

Analyses involving apo A-i and apo B

measure-ment were restricted to children fasting for 12 hours

prior to examination (n = 2,923), and compliance

was determined by interview on the morning of

examination. Apo A-I and apo B determinations

were not available for 2.4% (n = 69) of the fasting

children. Of those with apolipoprotein

measure-ments, 926 (32%) were white males, 907 (32%) were

white females, 478 (17%) were black males, and 543

(19%) were black females.

Physical

Examination

A physical examination was given by a physician,

and sexual maturation was determined by visual

assessment of secondary sex characteristics

accord-ing to the method of Tanner.26 The ratings for

sexual maturation ranged from 1 (no development)

to 5 (complete development) according to the stages

of female breast or male genitalia development.

Collection

of Blood

Specimens

Antecubital venous blood was collected in

Vacu-tamer tubes and allowed to clot for approximately

i#{189}hours. After centrifugation, sera were collected

in tubes containing thimerosal (Aldrich Chemical

Co, Milwaukee, WI) and sent in a cold-packed box,

by bus, to the New Orleans Core Lipid Laboratory

of the National Research and Demonstration

Cen-ter-Arterioscierosis where it was kept at 4#{176}C.The

following day the sera were analyzed for lipids,

lipoproteins, and apo B, and the remaining samples

were kept frozen at -20#{176}Cuntil apo A-I

measure-ments were made (the samples remained stored 9

to 15 months).

A second independent blind duplicate blood

sam-pie was collected at each screening day on a 10%

random subsample of the children to estimate

mea-surement errors.

Serum

Lipid and Lipoprotein Cholesterol

Analyses

Cholesterol and triglyceride contents of whole

serum were determined in a Technicon

Auto-Analyzer II according to the laboratory manual of

the Lipid Research Clinics Program.27 The

labora-tory has been designated as standardized by the

Centers for Disease Control in Atlanta. An

isopro-panol extract of the sample was used for the

deter-minations. A serum calibrator, provided by the

Centers for Disease Control, was used to convert

the cholesterol values obtained by the

Auto-Analyzer II to the reference method of Abell et al.28

Serum VLDL-C, LDL-C, and HDL-C were

mea-sured by a combination of heparin-calcium

precip-itation and agar-agarose gel electrophoresis

proce-dures. A detailed description of this method,

in-cluding measurement errors and its application in

the Bogaiusa Heart Study, has been reported.9 The

specificity and quantitative aspects of the method

for the precipitation of apo B-containing

lipopro-teins have been well documented.29’3#{176}

Apolipoprotein

Assay

The levels of apo B and apo A-I in whole serum

were assayed by the electroimmunoassay procedure

of Laurell.3’ Antibodies to LDL (density 1.03 to

1.05 g/mL) and apo A-I (prepared by the procedure

of Miller et a132) raised in goats were used. The

electroimmunoassay for apo B was performed with

the use of antibody in 1.2% (w/v) agarose gel,

Tris-tricine buffer pH 8.6 at 6 V/cm for five hours. No pretreatment of samples and standards was carried out. In contrast, conditions for apo A-I were altered:

Electrophoresis was performed in 1.8% (w/v)

(3)

TABLE 1. Measuremen Determinations: Bogalusa

t Error for Serum Apolipoprotein B and Apolipoprotein A-I

Heart Study

Variable No. of

(Blind)

Mean (mg/dL) Measurement Error

SD Coefficient of

Variation

(%)

Sample 1 Sample 2

Apolipoprotein B 319 86.3 86.4 4.6 5.4

Apolipoprotein A-I 319 141.4 141.0 8.8 6.3

of samples, and standards were treated with 8 M

urea and 1% Nonidet P-40 detergent (final

concen-tration).33 Frozen aliquots from a pooled serum, in

which apo B and apo A-I were determined, served

as secondary standards.

Intraassay and interassay coefficients of

varia-tion ranged, respectively, 2.3% to 4.i% and 1.6% to

4.4% for apo B v 0% to 5.2% and 2.3% to 6.0% for

apo A-I. Measurement errors from the ‘blind

dupli-cate samples are given in Table 1. Because two

independent samples were collected from each of

319 individuals, the measurement error includes

errors associated with collection, processing, and

analysis of the samples, as well as with data

proc-essing. In addition to these quality control

meas-ures, the laboratory is participating in the

apolipo-proteins A-I and B standardization program of the

International Union of Immunological Societies,

Centers for Disease Control, and National Heart,

Lung, and Blood Institute.

No efforts were made to determine any possible

effect of frozen sample on apo A-I measurements.

Earlier studies have used frozen samples for

apoli-poprotein analysis.2224 Recently, Blum34 reported

that when samples were stored at -20#{176}Cas long as

8 years, there was no apparent relationship between

storage time and the values obtained for apo A-I.

Statistical Analysis

Because race and sex interactions were present,

ttests were performed within strata defined by race

or sex. Polynomial regression (using age, age2, and

age3 as independent variables) within each race-sex

group indicated three age groups differing according

to apolipoprotein changes. Piecewise regression

techniques35 were then used to calculate yearly

changes in predicted apolipoprotein levels within

each age group.

Differences in the magnitude of the Pearson

cor-relation coefficients were assessed after applying

Fisher Z transformation and assuming a variance

of i/(n -‘ 3)36 Race-, sex-, and age-specific Z scores

(relative deviates) for apo A-I and triglycerides were

calculated.’#{176} These standardized values were used

to assess the relationship between apo A-I and

triglycerides in each race-sex group, independently

of age. The possibility that race-related differences

in triglyceride and apo A-I levels could account for

apo A-I and triglyceride differences, respectively,

between the races was examined by matching age

and apo A-I or triglyceride levels. (Analysis of

co-variance was considered inappropriate because the

relationship between apo A-I and triglycerides

dif-fered between the races.)

RESULTS

Distributions and Mean Levels by Race and Sex

Distributions, mean levels, and both race- and

sex-related differences of the major serum lipids

and lipoprotein cholesterols remained essentially

the same as previously reported9”4 (data not

shown). Race- and sex-specific distributions of apo

A-I and apo B are shown in Figs 1 and 2; the mean

values of the apolipoproteins, along with HDL-C

and HDL-C/apo A-I ratio, are given in Table 2.

Because apo B is derived from both VLDL and

LDL, no ratio relating apo B to either of these

lipoprotein cholesterols was determined.

The distributions of apo A-I and apo B were

unimodal with median values almost identical with

the means. However, distributions of both

apoli-poproteins were skewed to the right, especially apo

B. Overall, levels of HDL-C and HDL-C/apo A-I

ratio were significantly higher in black children

than in white children, irrespective of sex. However,

apo A-I was significantly higher in blacks than in

whites only among boys. No race-related

differ-ences were noted for apo B. With respect to

sex-related differences, levels of HDL-C and HDL-C/

apo A-I ratio were significantly higher in white boys

than in white girls. In contrast, only black children

showed such significant sex-related differences for

apo A-I, with black boys showing higher values

than black girls. In both races, apo B was

signifi-cantly higher in girls than in boys.

Effect of Age

Race-, sex-, and age-specific mean levels of apo

A-I and apo B are shown in Fig 3. Age-related

changes were more apparent for apo A-I than for

apo B among all the four race-sex groups. For

(4)

o---o boys, N926 .‘-.. girls, N=907

o---o boys, N478 .-. girls, N543

Boys Girls

o---o whit#{149},N=926

.-. black, N=475

o---o whits, NSO7 S.-. black, N=543

140 180 220 0 60 100 140 180 220

Apo A-I, mg/di

50

WhIt#{149} Black

U

C

.

3

U.

40’

30’

20’

10

0-a

4080 #{149}120160200 0 40 80 120 160 200

Apo B, mg/dl

Fig 1. Distributions ofserum apolipoprotein (apo) A-I in boys and girls by race: Bogalusa Heart Study.

‘S

U C

3

U.

30

20

1

0-0 60 100

Fig 2. Distributions of serum apolipoprotein (apo) B in white and black children by sex:

Bogalusa Heart Study.

TABLE 2. Serum Levels

(HDL-C), and High-Density

of Apolipoprotein (Apo) A-I

Lipoprotein Cholesterol to A

, Apolipoprotein B, High-Density Lipoprotein Cholesterol polipoprotein A-I Ratio by Race and Sex*

Apo A-I (mg/dL)

Boys

-

-

.

-______

--White Black

(n = 926) (n = 478)

139 ± 21 144 ± 21

Girls Race

Differences

White Black (P.<)

(n = 907) (n = 543)

Sex Differences

(P<)

140 ± 21 141 ± 23 .001#{176} #{149}05b

Apo B (mg/dL) 83 ± 21 83 ± 20 86 ± 22 86 ± 21 NS .Old

HDL-C (mg/dL) 58 ± 20 66 ± 20 55 ± 21 64 ± 20 #{149}001d oc

HDL-C/apo A-I ratio 0.42 ± 0.13 0.46 ± 0.12 0.40 ± 0.14 0.45 ± 0.12 .00l’ .00i

(5)

140 A-I

120 whIti, N925

.-. black, N=475

100

80 S

60

Age (years)

Apo A-I

o---o whlt#{149}, N=907 .-. black, N=543

Apo S

5 7 9 11 13 15 17 5 7 9 11 13 15 17

Boys

5-9yrs.

10-l4yrs.

15-l7yrs.

Girls

5* **

I*5

5*I

-4 -2 0 2 4 -.4 -2 0 2 4

160 Boys Girls

V

E

.

. 1 C a

a

Fig 3.

Changes in serum apolipoprotein (apo) B and apo A-I levels in boys and girls by age and race: Bogalusa Heart Study.

5-8yrs.

9- l4yrs.

15-l7yrs.

Apo B Apo A-I

0 whlts

S

black

mg/di/y.ar (regression coefficient)

*p<O.05 **p<O.O1

Fig 4. Predicted yearly changes in serum apolipoprotein (apo) B and apo A-I levels in

boys and girls by race and age groups: Bogalusa Heart Study.

showed a progressive decrease in apo A-I levels

between the ages of 10 and 17 years.

Because apolipoprotein changes with age were

not linear, the relationship between these two

pa-rameters was estimated for specific age groups

based on piecewise regression technique. Predicted

yearly changes (milligrams per deciliter per year)

in apo A-I and apo B levels are shown in Fig 4.

Boys of both races showed significant yearly

incre-ments in apo A-I between the ages of 5 and 9 years

(2.2 mg for white boys v 4.1 mg for black boys) and

marked decrements between the ages of 10 and 14

years (-2.5 mg for boys of both races). The

declin-ing trend was reversed only in 15- to 17-year-old

black boys who showed significant yearly

incre-ments (3.4 mg). Among the girls, yearly changes in

apo A-I were significant for each age group only for

white girls whose values increased between 5 and 8

years (2.4 mg) and decreased between 9 and 14

years (-1.4 mg), followed by increases between 15

and 17 years (3.4 mg). Although black girls showed

similar trends in each age group, changes were

significant only in 15- to 17-year-olds (3.9 mg).

With respect to apo B, white girls showed a

significant yearly increase between the ages of 5

and 8 years (3.1 mg) followed by an equally

signif-icant decrease between the ages of 9 and 14 years

(-2.3 mg). Minimal changes were noted between

15 and 17 years of age in white girls. The yearly

changes by age group were not significant for other

race-sex groups.

The relationship of changes in HDL-C to changes

in apo A-I, with age, were evaluated in terms of

(6)

race-o---o whlt#{149}, N=926 .-. black, N=471

0 a

4

0 0. 4

(;)

-I a I C

a

a

o---o whlti, N=907 a-. black, N=543

S

0

5 . 7

.

9

.

1’l1315 17 0.55

I

Boys Girls

0.50’

0.45-0.40’

0.35

0.30

5 7 9 11 13 15 17

Age (years)

Fig 5.

Changes in high-density lipoprotein cholesterol (HDL-C) to apolipoprotein (apo)

A-I ratio in boys and girls by age and race: Bogalusa Heart Study.

TABLE 3. Serum Levels of Apolipoproteins (Apo) A-I and B by Sexual Maturation*

Tanner Stage Tanner Stage v

Apolipoproteinst

1 2 3 4 5

Apo A-I (mg/dL)

White boys 143 ± 21 139 ± 20 136 ± 20 130 ± 20 132 ± 19 -0.231

White girls 141 ± 21 137 ± 22 137 ± 20 136 ± 18 142 ± 19 -0.04

Black boys 144 ± 20 146 ± 21 146 ± 24 140 ± 25 144 ± 23 -0.01

Black girls 141 ± 22 138 ± 23 135 ± 22 142 ± 27 144 ± 23 -0.03

Apo B (mg/dL)

White boys 84 ± 21 86 ± 20 83 ± 22 78 ± 23 80 ± 24 -0.08

White girls 88 ± 22 89 ± 22 83 ± 21 78 ± 19 80 ± 20 -0.16

Black boys 83 ± 19 86 ± 21 83 ± 20 80 ± 20 81 ± 23 -0.05

Black girls 87 ± 22 85 ± 19 86 ± 23 86 ± 20 83 ± 19 -0.07

* Values are means ± SD.

t Pearson correlation coefficients.

:tP<.0001

§

P < .05.

specific mean ratios are shown in Fig 5. Boys from

both races showed a decrease in the ratio with age;

this trend was most pronounced in older white boys.

In girls of both races the ratio decreased between

the ages 5 and 1 1 to 12 years. Afterward, the ratio

increased until the age of 15 years, followed by

further decreases in white girls. Values in

17-year-old adolescents were lower than the values at 5

years of age in all race-sex groups except black

boys.

Effect

of Sexual

Maturation

Because adolescents of a given age express wide

variations in stage of sexual maturation, apo A-I

and apo B changes were also related to various

Tanner stages, an index ofphysiologic development

during adolescence (Table 3). Although secondary

sex characteristics are considered subjective, the

relationships with serum apo A-I and apo B can be

seen for Tanner stages. In adolescents the changes

of these apoproteins with maturation are quite

sim-ilar to those noted above with age, reflecting a close

association between developmental age and

chron-ologic age in the population as a whole. (Correlation

coefficients between age and Tanner stages for the

race-sex groups ranged from 0.79 to 0.87.) Of

par-ticular interest is the significant negative

relation-ship between apo A-I and sexual maturation seen

only in white boys. White children, especially girls,

showed an inverse association between apo B and

sexual maturation.

Relationship

to Serum

Lipids and Lipoprotein

Cholesterol

(7)

TABLE 4. Relationship of Apolipoproteins B and A-I

With Serum Lipids and Lipoprotein Cholesterol in White

(n = 1,830) and Black (n = 1,019) Children: Bogalusa

Heart Study*

ApoB ApoA-I

White Black White Black

Cholesterol

Total 0.77 0.761 0.39 0.37

Very low-density 0.48 0.38 -0.15 -0.04

lipoprotein

Low-density 0.93 0.92 0.06t 0

lipoprotein

High-density -0.36 -0.18 0.49 0.54

lipoprotein

Triglycerides 0.53 0.38 -0.13 0.01

Apo B 0.05t 0

* Pearson’s product-moment correlation coefficient.

tP< .05.

:I:P<.001.

§

Race difference, P < .01.

serum lipids and lipoprotein cholesterol levels in

black v white children is presented in Table 4. In

both races, apo B was strongly related to both

LDL-C and total cholesterol and less strongly to

VLDL-C and triglycerides. A significant negative

correla-tion was noted between apo B and HDL-C. The

magnitude of the correlation of apo B with

triglyc-erides, VLDL-C, and HDL-C was less strong in

black children.

Apo A-I was moderately correlated with HDL-C

and to a lesser extent with total cholesterol.

How-ever, the association of apo A-I to HDL-C was not

as pronounced as the relationship between apo B

and LDL-C. A plot of apo A-I v HDL-C showed

that at a given level of apo A-I there was a wide

range of corresponding HDL-C levels (data not

shown). Although apo A-I was inversely correlated

with VLDL-C and triglycerides in white children,

no association was noted in black children. The

inverse relations of HDL-C to VLDL-C and

tn-glycenides occurred, as previously reported,9 in both

black and white children, and the relationships

were relatively stronger in whites than in blacks

(data not shown).

Serum Triglycerides-Apo A-I Associations

Because both serum triglycerides and VLDL are

inversely related to HDL,9’37 the differences in apo

A-I levels between black and white boys (blacks>

whites) is apparently consistent with the difference

in triglycerides (whites > blacks). To ascertain

whether this metabolic inverse relationship

be-tween these variables was entirely responsible for

the black-white differences, mean levels of

triglyc-erides and apo A-I by race were assessed separately

in boys and girls over each decile for apo A-I and

triglyceride relative deviates, respectively.

The formula (x - iRSA)/SRSA was used to

stand-ardize every child’s serum apo A-I or triglycerides

to the respective race-, sex-, age-specific group

(RSA).’#{176}For example, 144 mg/dL was the mean

(isA) apo A-I for all 10-year-old white boys and 21

mg/dL, the standard deviation (SRSA). A

10-year-old white boy with apo A-I level of 200 mg/dL

would have a relative deviate of (200 - 144)/21 =

+2.67. The corresponding value for another boy in

the same RSA with an apo A-I level of 100 mg/dL

would be -2.10. After relative deviates were

calcu-lated for all children, they were grouped in deciles.

Over each decile mean apo A-I or triglycerides were

determined for each race-sex group. The data are

shown in Fig 6.

Both white boys and white girls showed a steady

decline in triglycerides and apo A-I across the

higher deciles for apo A-I and triglycerides,

respec-tively (Fig 6). No such trend was noted in black

children. In boys black-white differences in

tniglyc-enide levels were discernible only at lower apo A-I

relative deviates. In contrast, the race-related

dif-ference in apo A-I levels in boys was not apparent

at higher deciles of triglyceride relative deviates. In

girls, although the black-white difference in

triglyc-enides was seen throughout the entire apo A-I

dis-tnibution, no such difference in apo A-I was noted

in relation to triglyceride distribution.

To determine triglycenide-apo A-I associations in

boys of both races, matching analyses based on

triglycerides (or apo A-I) and age were performed.

Mean apo A-I or triglyceride levels were then

corn-pared between the races. The results, Table 5, show

that the differences in apo A-I between black and

white boys who were matched for triglycerides and

age approached statistical significance only when

their triglyceride levels were high. Conversely, the

black-white difference in triglycerides among boys

who were matched for apo A-I and age became

apparent only when their apo A-I levels were low.

Selected

Percentiles

To estimate the statistical normal limits for

serum apo A-I and apo B in the pediatric

popula-tion, fifth and 95th percentile values by race, sex,

and age were determined and given in Tables 6 and

7, respectively. In addition, tenth percentile value

for apo A-I and 90th and 75th percentile values for

apo B were included as a guideline for identification

of a larger number of individuals who might be

potentially at risk for developing coronary heart

disease later in life.38 In general, consistent with

the race-, sex-, and age-related trends, the

percent-ile values for apo A-I differed between the races.

(8)

Boys Girls

C---O whlt#{149}, N 926 --o white, N 907

a-. black, N 478 .-#{149} black, N 543

- 80 0.

___o

o--, a \___o_.o..

----O---O---’Y-60

40

‘S

, 20

C a

a

a

_________________________

0 r, ,

Apo A-I relative deviate deciles

I

::

130

C a

e

a 120

1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

Low HIgh Low High

Triglycerides relative deviate deciles

Fig 6.

Serum triglyceride-apolipoprotein (apo) A-I associations in children by race, sex,

and decile: Bogalusa Heart Study.

TABLE 5. Black-White Comparisons of Serum Triglycerides and Apolipoprotein A-I in

Matched Pairs*

Triglycerides Apolipoprotein A-I Age

(mg/dL) (mg/dL) (yr)

Triglycerides

53 mg/dL (261 pairs)t

White 41 ± 8 144 ± 21 9.7 ± 3.1

Black 42 ± 7 144 ± 21 9.7 ± 3.2

54 mg/dL (179 pairs)t

White 71 ± 16 140 ± 19 10.7 ± 3.7

Black 71 ± 15 144 ± 22 10.8 ± 3.7

Apolipoprotein A-I

141 mg/dL (215 pairs)t

White 59 ±

341:

126 ± 11 10.1 ± 3.7

Black 54 ± 2O 126 ± 11 10.1 ± 3.7

142 mg/dL (231 pairs)t

White 55 ± 27 158 ± 12 10.1 ± 3.2

Black 53 ± 34 158 ± 12 10.1 ± 3.1

* Pairs are matched on apolipoprotein A-I or triglycerides and age. Values are means ±

SD.

t

Median values.

:1:

P < .10 (paired t test).

between boys and girls, the magnitude ofwhich was 17 years of age. With respect to apo A-I,

race-dependent upon age. related difference (blacks > whites) is seen only

among boys, in agreement with earlier findings in

DISCUSSION

adults

by

Tyroler et al.23 These authors have also

The present study describes the race-, sex-, and shown that the black-white difference in apo A-I is

age-related patterns of serum apo A-I and apo B in not completely accounted for by differences in

(9)

TABLE 6. Selected Percentile Values for Serum Apolipoprotein A-I in Children by Race,

Sex, and Age: Bogalusa Heart Study

Race and Boys Girls

Age (yr) n 5th 10th 95th n 5th 10th 95th

White

5-7 242 107 112 176 243 105 112 176

8-9 152 112 116 176 166 109 112 176

10-11 180 112 115 176 186 107 112 176

12-13 156 102 112 176 144 96 112 170

14-15 135 99 112 162 107 112 112 170

16-17 60 96 103 170 61 112 116 175

Black

5-7 127 104 112 172 138 104 112 192

8-9 84 112 122 176 99 112 112 176

10-11 98 122 128 176 85 96 110 18.8

12-13 55 107 112 193 78 96 106 192

14-15 63 107 112 176 75 109 112 177

16-17 51 111 118 192 68 107 112 192

TABLE 7. Selected Percentile Values for Serum Apolipoprotein B in Children by Race,

Sex, and Age: Bogalusa Heart Study

Race and Boys Girls

Age (yr) n 5th 75th 90th 95th n 5th 75th 90th 95th

White

5-7 242 51 92 104 115 243 53 96 113 120

8-9 152 53 93 104 114 166 58 104 117 143

10-11 180 57 96 108 120 186 59 102 120 132

12-13 156 50 93 106 123 144 50 90 112 120

14-15 135 48 88 104 112 107 45 88 104 117

16-17 60 52 96 109 151 61 45 88 103 106

Black

5-7 127 49 96 104 112 138 52 96 109 120

8-9 84 54 96 106 128 99 54 96 114 120

10-11 98 54 96 104 113 85 53 102 117 137

12-13 55 48 90 108 117 78 54 91 108 116

14-15 63 44 92 106 117 75 49 104 114 117

16-17 51 47 90 114 162 68 50 92 115 133

relatively higher in adults than in children of both

races.

The present findings demonstrate that a

signifi-cant black-white difference in apo A-I persists

among boys with almost identical triglyceride levels

provided that their triglyceride levels were in the

upper range of the distribution (Table 5). On the

other hand, the race-related difference in

tniglyc-enides among boys with almost identical apo A-I

levels is seen at low apo A-I levels. Because

triglyc-enides are inversely related to apo A-I in white

children but not in black children, the black-white

differences in apo A-I and triglycerides are likely to

become apparent at high and low levels of

triglyc-enides and apo A-I, respectively. However, it is of

interest that in girls race-related differences in

triglycerides persist at all levels of apo A-I; the

trend is not noted for apo A-I either at low or high

levels of triglycerides (Fig 6). It appears that the

black-white difference in triglycerides among girls

may not be totally attributable to the metabolic

inverse relationship between HDL and VLDL.37’39

These observations raise the possibility of some

intrinsic metabolic differences between the two race

groups.

The sex- and age-related changes in children

indicate a tendency for black girls to have lower

apo A-I and for girls of both races to have higher

apo B levels. In contrast, adult men (older than 20

years of age) show lower levels of apo A-I and higher levels of apo B than women.2224’4#{176} The

character-istic adult pattern seems to emerge during the latter

part of sexual maturation.

Although the age- and puberty-related

observa-tions are cross-sectional, the observed changes of a

large population probably reflect longitudinal

trends. Previously noted cross-sectional decreases

in HDL-C levels in white boys undergoing sexual

maturation14”5 parallel HDL-C longitudinal

de-creases observed in a cohort of white males from

the same Boys from both races

(10)

5 and 9 years, followed by marked decrements

be-tween 10 and 14 years of age (Fig 4). Girls,

espe-cially white girls, showed similar trends during

these age intervals. Of particular interest are the

changes that occurred among the four race-sex

groups in 15- to 17-year-olds. White boys continued

to show decrements during this age interval,

whereas black boys and girls of both races showed

increasing apo A-I Levels. No such changes in apo

B, with age, are seen among the race-sex groups,

except in white girls who showed increases between

the ages of 5 and 8 years followed by decreases.

The relationship of sexual maturation (Tanner

stages) to apolipoprotein changes is discernible only

in white children, with boys and girls showing

in-verse associations, respectively, for apo A-I and apo

B (Table 3). Earlier studies of children from this

community have shown that black children of each

sex progressed through each Tanner stage at an

earlier age than did white children.42 The divergent

changes in apolipoproteins during sexual

matura-tion probably reflect underlying physiologic and

metabolic differences related to race and sex.

Ap-parently, endogenous sex hormones are having a

major influence on the lipoprotein profile in

ado-lescents.43’44 In addition, the well-documented

ef-fects of smoking, alcohol, and oral contraceptives

on lipoprotein levels in older adults have been

dem-onstrated in adolescents as well.45’46 It is worthwhile

to understand the contribution of intrinsic (or

ge-netic) v environmental factors to the observed

dif-ferences during this transition period.

The continued decrease of apo A-I in white boys

during the transition to adulthood parallels the

HDL-C decrease seen previously in this race-sex

group.’4”5 The black-white differences in

lipopro-tein makeup appear to continue through

adult-hood.23’47 Because HDL is considered to be

antiath-erogenic,4’6’7 the adverse changes of apo A-I, as well

as HDL-C in white males, may target this group

for accelerated atherosclerosis and future coronary

heart disease. The greater incidence of coronary

heart disease among white men than black men

seems to support such views.48

The relationships of apo A-I and apo B to lipids

in different lipoprotein cholesterol fractions are in

the expected directions, given the metabolic and

functional associations among them.’7’37’39 The

oh-served black-white differences in the above

rela-tionships suggest differences in lipoprotein makeup

between the two groups. For example, relatively

lower levels of VLDL-C (or triglycerides) in black

children without any difference in apo B levels

would result in lower correlation between these

variables in the black compared to white children.

The finding that the relation of apo A-I to

HDL-C in children is not strong indicates the possibility

of heterogeneity among HDL particles, eg,

occur-rence of varying proportions of HDL2 and

HDL3.49’5#{176}It is known that HDL2 carries about

twice as much cholesteryl ester molecules per mole

of apo A-I compared to HDL3 and that the HDL

components, cholesterol and apo A-I, arise

inde-pendently through metabolic interconversions of

lipoproteins.37 Unlike HDL3, HDL2 differs

mark-edly among individuals and accounts for the

varia-bility of total HDL.50’5’ Therefore, any variability

in HDL subfractions among individuals is expected

to result in various levels of cholesterol for a given

amount of apo A-I. The variability in HDL-C, in

relation to apo A-I, may also be in part due to the

exchange of cholesteryl esters for triglycerides

be-tween HDL and VLDL, resulting in a decrease in

HDL-C with increasing triglycerides (VLDL).24’52

The possibility of race- and sex-related

differ-ences in HDL subpopulations is further supported

by the finding that the HDL-C/apo A-I ratio differs

by race (black > white) and by sex (boys > girls,

especially among white children). A higher ratio of

HDL-C/apo A-I suggests an increase in HDL2 in

proportion to HDL3.22 Recently, Tyroler et al23

found higher apo A-I/apo A-Il ratios in adult

blacks, especially men. Because the apo A-I/apo

A-II ratio is higher in HDL2 than in HDL3,53 these

authors hypothesized that HDL2 may be relatively

higher among blacks. Our results in children seem

to support this view. Although women are known

to have higher HDL2 than men,37’51 our findings

that younger white boys have a higher HDL-C/apo

A-I ratio than younger white girls suggest an

op-posite pattern in childhood. That marked changes

occur with HDL subfractions during childhood is

seen from the alterations in HDL-C/apo A-I ratio

with age.

Although the fifth and 95th percentiles may be

statistically valid normal population limits, they

are arbitrary and do not necessarily represent the

optimal levels with respect to coronary heart

dis-ease risk. It should be noted that some of the age-,

race-, and sex-specific percentiles provided here are

based on a relatively small number of observations.

Additional comparative data in pediatric

popula-tions living in different cultural and geographic

environments within the country may be necessary

for obtaining more accurate normal limits. Because

coronary heart disease is widely prevalent in the

population at large, less rigid limits are outlined by

including 90th and 75th percentiles for apo B and

the tenth percentile for apo A-I. These observations

will serve as baselines for comparison with other

(11)

interven-tion, especially when a family history of coronary heart disease is present.

ACKNOWLEDGMENTS

This research was supported by grant HL 02942 from the National Heart, Lung, and Blood Institute of the Public Health Service and grant HL 15103 from the National Research and Demonstration

Center-Arterio-sclerosis.

We are grateful to the children of Bogalusa and their

parents, without whom this work would not have been possible. We thank the Bogalusa Heart Study staff for

data collection and the National Research and

Demon-stration Center-Arteriosclerosis Core Laboratory staff, especially Rajini Sharma and Mildred Caro, for technical

assistance.

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Oxford University Press, 1980, pp 1-453

2. Lauer RM, Shekelle RB (eds): Childhood Prevention of Atherosclerosis and Hypertension. New York, Raven Press,

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8. Lauer RM, Connor WE, Leaverton PE, et a!: Coronary heart disease risk factors in school children-The Muscatine Study. J Pediatr 1975;86:697-706

9. Srinivasan SR, Frerichs RR, Webber LS, et a!: Serum lipo-protein profile in children from a biracial community-The Bogalusa Heart Study. Circulation 1976;54:309-318 10. Ellefson RD, Elvebach LR, Hodgson PA, et al: Cholesterol

and triglycerides in serum lipoproteins of young persons in Rochester, Minnesota. Mayo Clin Proc 1978;53:307-320

11. Tamir I, Heiss G, Glueck CJ, et al: Lipid and lipoprotein distributions in white children ages 6-17 years: The Lipid Research Clinics Program Prevalence Study. J Chronic Dis

1981;34:27-39

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Child 1979;133:1049-1057

13. Berenson GS, Foster TA, Frank GC, et a!: Cardiovascular disease risk factor variables at the preschool age-The

Bo-galusa Heart Study. Circulation 1978;57:603-612

14. Berenson GS, Srinivasan SR, Cresanta JL, et a!: Dynamic changes of serum lipoproteins in children during adolescence and sexual maturation. Am J Epidemiol 1981;113:157-170 15. Morrison JA, Laskarzewski PM, Rauh JL, et al: Lipids,

lipoproteins and sexual maturation during adolescence: The Princeton Maturation Study. Metabolism 1979;28:641-649 16. Morrison JA, deGroot I, Edwards BK, et al: Lipids and

lipoproteins in 927 school children, ages 6 to 17 years. Pediatrics 1978;62:990-995

17. Havel BA, Goldstein JL, Brown MS: Lipoproteins and lipid transport, in Bondy CPK, Rosenberg LE (eds): Metabolic Control and Disease. Philadelphia, WB Saunders, 1980, pp

393-494

18. Glomset JA: The plasma lecithin:cholesterol acyltransferase reaction. J Lipid Res 1968;9:155-167

19. Fielding CJ, Fielding PE: Cholesterol transport between cells and body fluids. Med Clin North Am 1982;66:363-373 20. Avogaro P, Bittolo BG, Cazzolato G, et al: Are apoproteins

better discriminators than lipids for atherosclerosis? Lancet

1979;1:901-903

21. Brunzell JD, Sniderman AD, Albers JJ, et a!: Apoproteins

B and A-I and coronary artery disease in humans.

Arterio-sclerosis 1984;4:79-83

22. Albers JJ, Wahi PW, Cabana VG, et a!: Quantitation of apolipoprotein A-I of human plasma high density lipopro-tein. Metabolism 1976;25:633-644

23. Tyroler HA, Heiss G, Schonfeld G, et al: Apolipoproteins A-I, A-Il, and C-Il in black and white residents of Evans County. Circulation 1980;62:249-254

24. Phillips NR, Have! BA, Kane JP: Serum !ipoprotein A-I levels: Relationship to !ipoprotein lipid levels and selected demographic variables. Am J Epidemiol 1982;116:302-313

25. Croft JB,’ Webber LS, Parker FC, et al: Recruitment and participation of children in a long-term study of cardiovas-cular disease: The Bogalusa Heart Study. Am J Epidemiol 1984;120:436-448

26. Tanner JM: Growth at Adolescence, ed 2. Oxford, Blackwell Scientific Publications, 1962

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for the estimation of total cholesterol in serum and demon-stration of its specificity. J Biol Chem 1952;195:357-366 29. Srinivasan SR, Ellefson RD, Whitaker CF, et a!: Lipoprotein

cholesterol in the serum of children, as determined inde-pendently by two different methods. Clin Chem

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1980;26:1548-1553

31. Laurel! CB: Electroimmunoassay. Scand J Clin Lab Invest 1972;29(suppl 124):21-37

32. Miller JP, Mao SJT, Patsch JR, et al: The measurement of apo!ipoprotein A-I in human plasma by electroimmunoas-say. J Lipid Res 1980;25:775-789

33. Roheim PS, Vega GL: Electroimmunoassay of apolipopro-tein A-I, in Lippel K (ed): Report of the High Density

Lipoprotein Methodology Workshop. US Department of Health, Education, and Welfare publication No. (NIH) 79-1661. National Institutes of Health, 1979:241-248

34. Blum CB: Radioimmunoassay of apolipoproteins, in Lippel

K (ed): Proceedings of the Workshop on Apoprotein Quanti-fication. US Department of Health, Education, and Welfare publication No. (NIH) 83-1266. National Institutes of Health, 1983, p 243

35. Neter J, Wasserman W: Applied Linear Statistical Models.

Homewood, IL, RD Irwin mc, 1974, pp 313-317

36. Snedecor GW: Statistical Methods. ed 7. Ames, IA, Iowa State University Press, 1980, pp 185-188

37. Nichols AV: Human serum !ipoproteins and their

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38. Rifkind BM, Sega! P: Lipid Research Clinics Program ref-erence values for hyperlipidemia and hypolipidemia. J Am Med Assoc 1983;250:1869-1872

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Sci 1980;348:30-44

40. Alaupovic P, McConathy W, Fesmire J: Apolipoprotein pro-files of dyslipoproteinemic states, in Lippel K (ed):

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ado-lescence: The Bogalusa Heart Study. Metabolism 1985; 34:396-403

42. Foster TA, Voors AW, Webber LS, et a!: Anthropometric and maturation measurements of children, ages 5-14 years, in a biracial community-The Bogalusa Heart Study. Am J Clin Nutr 1977;30:582-591

43. Laskarzewski PM, Morrison JA, Gutai J: High and low density lipoprotein cholesterol in adolescent boys: Relation-ship with endogenous testosterone, estradiol and Quetelet

index. Metabolism 1983;32:262-271

44. Srinivasan SR, Sundaram GS, Williamson GD, et a!: Serum lipoproteins and endogenous sex hormones in early life: Observations in children with different !ipoprotein profiles. Metabolism 1985;34:861-867

45. Webber LS, Hunter SM, Baugh JG, et a!: The interaction of cigarette smoking, oral contraceptive use, and cardiovas-cular risk factor variables in children: The Bogalusa Heart Study. Am J Public Health 1982;72:266-274

46. Morrison JA, Kelly K, Mellies M, et a!: Cigarette smoking, alcohol intake, and oral contraceptives: Relationships to lipids and lipoproteins in adolescent school-children. Metab-olism 1979;28:1666-1670

47. Tyroler HA, Hames CG, Krishan I, et a!: Black-white

dif-ferences in serum lipids and lipoproteins in Evans County.

Prey Med 1975;4:541-549

48. Tyroler HA, Heyden 5, Bartel A, et al: Blood pressure and cholesterol as coronary heart disease risk factors. Arch In-tern Med 1971;128:907-914

49. Patsch JR, Sailer 5, Kostner G, et a!: Separation of the main lipoprotein density classes from human plasma by rate-zonal ultracentrifugation. J Lipid Res 1974;15:356-366 50. Anderson DW, Nichols AV, Forte TM, et a!: Particle

distri-bution of human serum high density lipoproteins. Biochim Biophys Acta 1977;493:55-68

51. Anderson DW, Nichols AV, Pan 55, et a!: High density lipoprotein distributions: Resolution and determination of three major components in a normal population sample.

Atherosclerosis 1978;29:161-179

52. Srinivasan SR, Webber LS, Berenson GS: Lipid composition

and interrelationships of major serum lipoproteins:

Obser-vations in children with different lipoprotein profiles: Bo-galusa Heart Study. Arteriosclerosis 1982;2:335-345

53. Chueng MC, Albers JJ: Distribution of cholesterol and

apo-lipoprotein subfractions separated by CsC1 equilibrium gra-dient ultracentrifugation: Evidence for HDL subpopulations with differing A-I/A-Il molar ratios. J Lipid Res 1978;20:58-65

ANNOUNCEMENT

The European Society for Pediatric Research will hold its next meeting in

Groningen, The Netherlands, Sept 7-10, 1986. The following Working Groups

will join the meeting: Paediatric Allergy and Clinical Immunology, Paediatric

Pharmacology, and Perinatal and Paediatric Microcirculation. The main topics

are Nutrition and Metabolism, Hepatic Metabolism, Fetal and Neonatal

Me-tabolism, Developmental Neurology, Genetics Immunology, Pharmacology,

Mi-crocirculation, and Oncology.

For young investigators, particularly from Eastern Europe, travel bursaries

are available. For information and participation contact: J. Fernandes,

Depart-ment of Paediatrics, University Hospital, 59 Oostersingel, 9713 EZ Groningen,

(13)

1986;78;189

Pediatrics

Gerald S. Berenson

Sathanur R. Srinivasan, David S. Freedman, Chakravarthi Sharma, Larry S. Webber and

Bogalusa Heart Study

Serum Apolipoproteins A-I and B in 2,854 Children From a Biracial Community:

Services

Updated Information &

http://pediatrics.aappublications.org/content/78/2/189

including high resolution figures, can be found at:

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http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

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(14)

1986;78;189

Pediatrics

Gerald S. Berenson

Sathanur R. Srinivasan, David S. Freedman, Chakravarthi Sharma, Larry S. Webber and

Bogalusa Heart Study

Serum Apolipoproteins A-I and B in 2,854 Children From a Biracial Community:

http://pediatrics.aappublications.org/content/78/2/189

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

Fig 2.Distributionsofserumapolipoprotein(apo)Binwhiteandblackchildrenbysex:BogalusaHeartStudy.
Fig 4.Predictedboysyearlychangesinserumapolipoprotein(apo)BandapoA-Ilevelsinandgirlsbyraceandagegroups:BogalusaHeartStudy.
Fig 5.Changesin high-densitylipoproteincholesterol(HDL-C)to apolipoprotein(apo)A-Iratioin boysandgirlsby ageandrace:BogalusaHeartStudy.
Fig 6.Serumtriglyceride-apolipoprotein(apo)A-Iassociationsinchildrenbyrace,sex,anddecile:BogalusaHeartStudy.

References

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