© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Determinants of Lipid Level Variability in French-Canadian Children With Familial Hypercholesterolemia
From the Medical Genetics Service, Department of Pediatrics (M.L., L.A., J.C.F.-F., N.B.), the Department of Clinical Biochemistry (E.E.D.), and the Department of Nutrition (E.L.), Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
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Abstract |
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Abstract—The wide variability in the biochemical expression of familial hypercholesterolemia (FH) is only partly explained by mutational heterogeneity in the low density lipoprotein receptor (LDLR) gene. In the current study, we measured this biochemical variability in a group of children heterozygous for the >15-kb LDLR gene deletion (n=67) and examined the contribution of apolipoprotein (apo) E and B allelic variations to this phenotypic variability. Variances of total cholesterol (TC), LDL-C, and apoB concentrations and of the ratio of TC to high density lipoprotein cholesterol (HDL-C) were increased in FH subjects compared with controls. However, after taking the means into account, the coefficients of variation showed that the variability of LDL-C and apoB concentrations was smaller for FH than for controls and that the variability of TC and of the ratio TC to HDL-C was similar between both groups. The
2/3 genotype was associated with
lower mean TC, LDL-C, and apoB concentrations in FH. The magnitude of
this effect was smaller in controls than in FH. Indeed, the percentages
of total variance of TC, LDL-C, and apoB attributable to the apoE locus
were 19.9%, 18.1%, and 11.8%, respectively, in FH cases and 5.9%,
7.4%, and 6.0%, respectively, in controls. We did not detect any
effect of the apoB insertion/deletion polymorphism on lipid traits
in FH children. However, in controls, we observed a strong interaction
between apoE and apoB genotypes on apoB concentrations and on
TC to HDL-C ratios. Our study reemphasizes the important role of apoE
in lipid metabolism and illustrates that the effects of
allelic variations on lipid traits are context dependent.
Key Words: familial hypercholesterolemia • children • apoE • apoB • allelic variations
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Introduction |
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Heterozygous familial hypercholesterolemia (FH), an autosomal dominant disorder due to a defect in the LDL receptor (LDLR) gene, is biochemically characterized by a large increase in plasma total cholesterol (TC) and LDL cholesterol (LDL-C) concentrations. The wide variability in FH biochemical expression has been explained by mutational heterogeneity, variations in the wild-type LDLR gene allele, allelic variations at other gene loci, and environmental factors.1 2 It is therefore important to examine the range of phenotypic variability associated with a single LDLR gene mutation. Few have had this opportunity because of the lack of sufficiently large groups of patients carrying the same mutation.3 4 5 Owing to a founder effect, French Canadians from Quebec show a higher frequency of FH (1/270) compared with most Western countries (1/500). The >15-kb deletion that removes the promoter and the first exon of the gene accounts for
60% of the mutant alleles found in
French-Canadian FH
heterozygotes.2 Our first
objective was to measure the biochemical variability seen in a large
group of children heterozygous for the >15-kb deletion and to compare
this variability to that found in controls.
Apolipoprotein (apo) E plays a central role in the
metabolism of cholesterol and
triglyceride (TG). The apoE gene locus on chromosome 19 is
polymorphic with 3 common alleles, 2, 3, and 4,
encoding the 3 different protein isoforms E2, E3, and E4, respectively.
The E2 and E4 variants differ from the more common E3 variant by a
single amino acid substitution. These substitutions affect ligand
binding of TG-rich lipoproteins to their
receptors.6 In healthy
adults, between 4% and 8% of the total variance in plasma LDL-C
concentrations can be attributed to the common apoE
polymorphism.6 7
ApoB is the major apolipoprotein of chylomicrons, VLDL, IDL, LDL, and
lipoprotein(a) particles. The apoB gene located on chromosome 2 has
numerous polymorphic sites, among which are those due to an
insertion (Ins) or a deletion (Del) of 9 base pairs, which produces a
difference of 3 amino acids in the signal peptide (for reviews, see
Humphries and Talmud8 and
Vedie et al9 ). This
polymorphism may have functional importance, as in vitro expression
studies have shown that the deletion variant mediates inefficient
translocation into the endoplasmic reticulum relative to the insertion
variant.10 Variations in
plasma lipid concentrations have been found associated with this
polymorphism. Therefore, our second objective was to examine the
contribution of apoE and apoB allelic variations to the phenotypic
variability of FH in children.
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Methods |
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Subjects
Subjects with heterozygous FH were selected from consecutive patients referred to the lipid clinic at Hôpital Sainte-Justine. The criteria for inclusion were (1) heterozygosity for the >15-kb LDLR gene deletion;1 (2) age 18 years or less; (3) absence of diabetes mellitus or kidney, thyroid, or hepatic disorders; (4) no intake of medications affecting lipoprotein metabolism, including oral contraceptives; and (5) no familial relationship up to the third degree or more. The subjects’ clinical and biochemical characteristics were those from their first visit at our lipid clinic. A family history of premature atherosclerosis was defined as coronary or peripheral vascular disease at or before the age of 55 years in a parent, grandparent, aunt, or uncle. Pubertal status was assessed according to Tanner stages, and subjects were classified as prepubertal (Tanner 1) or pubertal (Tanner 2 to 5).
Control subjects were recruited from patients undergoing minor elective surgery at Hôpital Sainte-Justine. The criteria for inclusion were (1) French-Canadian ancestry at history; (2) criteria 2, 3, and 4 as described above for FH; (3) no personal or parental history of hyperlipidemia; (4) no acute serious disease 3 months or less before the surgery; and (5) no family history of premature atherosclerosis. The study was approved by the hospital Ethics Committee, and informed consent was obtained from the parents and/or patients.
Laboratory Analyses
After a 12-hour overnight fast, blood samples were
collected on 1 mg/mL EDTA. TC and TG were determined enzymatically with
a commercial kit (Boehringer Mannheim). HDL-C was
measured after precipitation of VLDL and LDL with phosphotungstic acid.
LDL-C was calculated by using the Friedewald
equation.11 Plasma
concentrations of apoA1 and B were assessed by nephelometry equipped
with a commercial standard (Hoechst-Roussel).
Genomic DNA was prepared from white blood cells as described earlier.1 We used polymerase chain reaction (PCR) amplification of the appropriate DNA fragment followed by digestion of the amplification product with HhaI (Gibco BRL) to determine common apoE genotypes.12 The Ins/Del polymorphism was visualized directly after PCR amplification of exon 1 of the apoB gene and 8% polyacrylamide gel electrophoresis of the PCR products.13
Statistical Analyses
Statistical analyses were performed with SAS
statistical software (release 6.12, SAS Institute Inc). To ensure that
both groups (FH and control) were balanced with respect to the study
characteristics, Student’s t
tests or 
2 tests were performed,
depending on the nature of the characteristic under study (continuous
or categorical variable). Means and variances of plasma lipid and
apolipoprotein concentrations were compared between both groups by
using Student’s t tests and
Levene’s tests, respectively. Coefficients of variance (CVs)
were compared as described in
Sachs.14 All
analyses comparing TG concentrations were performed with
natural logarithm–transformed values; however, crude values are
presented in the Tables. The effect of covariates on plasma
lipid and apolipoprotein concentrations was studied by Pearson’s
coefficients of correlations (continuous variables) or Student’s
t tests (categorical
variables).
In both groups, apoE allele frequencies were estimated
by the gene counting method. Between-group allele and
genotype frequency distributions were compared by a
2 test. For each group (FH and control),
we performed a 1-way ANOVA and Levene’s tests to compare means and
variances, respectively, of plasma lipids of subgroups of subjects
divided according to their apoE genotype. When required,
Fisher’s least-significant-difference multiple-comparisons procedure
was used to detect subgroup differences. For each lipid trait, the
variance attributable to genotypic differences was computed as
described by Sing and
Davignon.15 A 2-way ANOVA
was used to simultaneously study groups of subjects divided
according to (1) their LDLR genotype (FH and control) and apoE
genotype, (2) their sex and apoE genotype, and (3)
their pubertal status and apoE genotype. Similar
analyses were performed for the apoB Ins/Del genotype.
Finally, for each group (FH and control), a 2-way ANOVA was used to
simultaneously study groups of subjects divided according
to their apoE and apoB
genotypes.
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Results |
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We studied a total of 67 unrelated children heterozygous for the >15-kb LDLR gene mutation and 241 controls. Table 1
shows the characteristics of the study
participants. Both groups were similar with respect to sex
distribution, age, and weight. As requested by protocol, none took oral
contraceptives. Family history of premature
atherosclerosis was recorded in 83.6% of FH
children and was absent in controls.
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Means, variances, and CVs of plasma lipid and apolipoprotein
concentrations are presented in
Table 2. As expected, in FH children the mean values of TC,
LDL-C, apoB, and of the ratio TC to HDL-C were significantly increased
compared with those in controls. The FH group had reduced mean
concentrations of HDL-C and apoA1 and an elevated mean concentration of
TG. Variances of TC, LDL-C, and apoB concentrations and of the TC to
HDL-C ratio were increased in FH subjects compared with controls.
However, after taking the means into account, the CV showed that the
variability of LDL-C and apoB concentrations was smaller for FH
subjects than for controls and that the variability of TC and of the
ratio TC to HDL-C was similar between FH and controls. Variances and
CVs of HDL-C, apoA1, and TG concentrations were statistically similar
between both groups.
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Heterogeneity in the biochemical expression of FH could not be explained by an effect of sex (probability value for comparisons between males and females=0.6525, 0.2971, and 0.7991 for TC, LDL-C, and apoB, respectively), age (r=0.0539, 0.0453, and 0.091 for correlations with TC, LDL-C, and apoB, respectively; P>0.05 for all), and pubertal status (probability value for comparisons between prepubertal and pubertal=0.6495, 0.6412, and 0.7152 for TC, LDL-C, and apoB, respectively). ApoB concentrations of FH subjects were loosely correlated with body mass index (r=0.2730, P=0.0348); there were no statistically significant correlations between TC (r=0.2041, P=0.1003) or LDL-C (r=0.2213, P=0.0789) and body mass index. Similarly, no statistically significant effect of sex, age, or weight on the concentrations of TC, LDL-C, and apoB could be detected in controls (data not shown). TG concentrations and the TC to HDL-C ratios were correlated with body mass index in FH subjects (r=0.3599 and 0.3361, respectively; P<0.05 for both) and with weight in controls (r=0.3846 and 0.2445, respectively; P<0.05 for both; body mass index data were not available for controls). We detected a significant correlation between TG concentrations and age in controls (r=0.2707, P=0.001) but not in FH subjects (r=0.1092, P=0.3827).
We next examined the contribution of apoE allelic variations
to the phenotypic variability of FH and compared these results to that
found in controls. There were no significant differences in apoE
allele or genotype frequency distributions between FH
subjects and controls (P=0.745
and 0.425, respectively). Because of their low frequency, individuals
with the genotypes 2/4 (FH, n=0; control, n=6) or 4/4
(FH, n=1; control, n=4) were excluded from subsequent analyses.
For all lipid and apolipoprotein traits examined, we detected no
significant interaction between sex and apoE genotype in FH and
controls or between pubertal status and apoE genotype in FH
(data on pubertal status were not available for controls). Therefore,
sex and pubertal status were not taken into consideration in subsequent
analyses.
The mean concentrations of TC, LDL-C, and apoB were the
lowest in FH children with the 2/3 genotype
(Table 3). These observations reached statistical
significance for TC and LDL-C values
(P<0.05 for comparisons
between 2/3 and 3/3 subjects and between 2/3 and 3/4
subjects); after apoB concentrations had been adjusted for body mass
index, they also showed significant differences. No significant
differences were seen between FH individuals with the 3/3 and 3/4
genotypes. Mean concentrations of HDL-C, apoA1, and TG and the
mean ratio of TC to HDL-C were similar among FH children with different
apoE genotypes. This conclusion remained unchanged after
adjustment for body mass index of TG concentrations and of TC to HDL-C
ratios. No significant differences were detected between variances of
lipids and apolipoproteins in FH subjects with different apoE
genotypes.
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In controls, when compared with 3/3 and 3/4, the
3/2 genotype had a significant lowering effect on mean TC,
LDL-C, and apoB concentrations and on the mean TC to HDL-C ratio
(P<0.05 for all). Although the
direction of the effect was similar in FH and controls, 2-way ANOVA
(apoE and LDLR genotypes) showed a significant interaction for
mean TC and LDL-C concentrations
(P=0.0009 and 0.0204,
respectively), suggesting different effects of apoE isoforms in each
group. No significant interactions were detected for mean apoB, HDL-C,
apoA1, and TG concentrations or for TC to HDL-C ratios
(P=0.2585, 0.1632, 0.2425,
0.5916, and 0.7417, respectively). Mean concentrations of HDL-C, apoA1,
and TG were similar among controls with different apoE
genotypes. These conclusions remained unchanged after
adjustment of TG and HDL-C concentrations and of TC to HDL-C ratios by
age and weight. Variances of TC and LDL-C values and of TC to HDL-C
ratios were significantly different between controls with different
apoE genotypes, the group with the 3/4 genotype
having the largest variance when compared with the 3/2 and 3/3
groups.
Table 4 presents the percentage of total variance of
lipid and apolipoprotein concentrations attributable to the apoE locus
in FH and controls.
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Third, we examined the contribution of apoB allelic
variations to the phenotypic variability of FH. Data from 74 FH
children were available for this portion of the study (67 previously
described and 7 newly diagnosed). There were no differences in apoB
Ins/Del allele or genotype frequency distributions between
FH subjects and controls
(P=0.965 and 0.129,
respectively). With the exception of TG concentrations, for all other
lipid and apolipoprotein traits examined, we did not detect any
significant interactions between sex and apoB genotype or
between pubertal status and apoB genotype. Therefore, sex and
pubertal status were not taken into consideration in subsequent
analyses.
Table 5 shows lipid and apolipoprotein levels with respect
to apoB Ins/Del genotypes. Variances of TG concentrations and
of TC to HDL-C ratios were significantly different between FH groups
with different apoB genotypes. We did not detect any other
statistically significant influence of apoB genotypes on means
or variances of all lipid and apolipoprotein variables examined in
FH. No further differences were observed after adjustment of lipid and
apolipoprotein values for body mass index.
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Compared with the apoB Ins/Del genotype, the apoB Ins/Ins genotype had a significant lowering effect on mean LDL-C and apoB concentrations and on the mean TC to HDL-C ratio in controls. No further differences were observed after adjustment of lipid and apolipoprotein values for weight and age. We observed a significant interaction between apoB genotype and LDLR genotype for mean TC, LDL-C, and apoB concentrations (P=0.0308, 0.0010, and 0.0181, respectively), suggesting different effects of the apoB genotype in each group. No such interaction was detected for mean HDL-C, apoA1, and TG concentrations or for mean TC to HDL-C ratios (P=0.9746, 0.1632, 0.5763, 0.2808, and 0.2228, respectively). Variances of all lipid and apolipoprotein variables examined were similar between control groups with different apoB genotypes.
Finally, we looked for possible interactions between apoE
and apoB genotypes in FH and controls. Because the numbers of
subgroups were too small, subjects with the apoB Del/Del
genotype were excluded from this analysis. For all
lipids and apolipoproteins examined, no interactions were detected in
FH (data not shown). However, in controls, strong interactions were
observed for apoB concentrations and for TC to HDL-C ratios
(P=0.0169 and 0.0463,
respectively). Indeed, no significant effect of apoE genotype
could be seen in those carrying the Ins/Ins genotype, whereas a
significant influence of apoE genotype could be detected in
those carrying the apoB Ins/Del genotype
(Table 6). No interaction effects were observed for other
lipid or apolipoprotein variables in
controls.
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Discussion |
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Our data illustrate that the phenotype of a "simple" monogenic disorder such as FH is in fact a complex trait. Indeed, phenotypic variability as assessed by measures of plasma concentrations of TC, LDL-C, and apoB was significantly greater among FH children than controls even when all affected children carried the same mutation. However, when means are taken into account by computing CVs, the variability of LDL-C and apoB concentrations proved to be smaller in the presence of the >15-kb deletion than in its absence. Similar observations were reported in French-Canadian adults carrying the same mutation.5 The subjects chosen for our study were unrelated to each other up to the third degree or more to minimize the selection bias pertaining to their common genetic background, thus providing a better estimate of the phenotypic variability associated with this specific mutation. The variability observed is a minimum estimate because all patients were referred to a specialized lipid clinic owing to a family history of hyperlipidemia and/or premature arteriosclerosis. Some heterozygotes may not come to medical attention because of a milder phenotype.
By comparison with adults, children are less influenced by
confounding environmental factors such as alcohol consumption, use of
medication, and the presence of undetected diseases. They may therefore
be better subjects in whom to identify genetic factors involved in
phenotypic variability. Moreover, subjects carrying the >15-kb
deletion are functional hemizygotes. Therefore, variable
interaction between the mutant gene product and its ligand or
between the mutant gene product and the wild-type gene product
cannot influence phenotypic expression. This characteristic should
further facilitate the identification of other genetic factors involved
in phenotypic variability. We found that the 2/3 genotype
was associated with lower mean TC, LDL-C, and apoB concentrations in FH
children. This effect was not sex-specific. Ferrieres et
al7 showed a similar effect
in French-Canadian FH women but not in men. Tonstad et
al16 did not detect any
influence of apoE genotype on lipid levels of Norwegian FH
children. To our knowledge, this is the only study done in FH children
that is available for comparison. Other studies done in various adult
populations with FH reported an influence of the apoE genotype
on TC and/or LDL-C in
some3 17 18
but not all of
them.4 19 20
It appears that in FH, different environmental and genetic backgrounds
may modulate the effect of the apoE polymorphism.
Although the 2/3 genotype was also associated
with significantly lower mean TC, LDL-C, and apoB concentrations in
control children, the magnitude of the effect was smaller than that
observed in FH children. Again, no sex-specific effect was detected. As
in adults,6 studies done in
healthy pediatric populations uniformly showed an influence of the apoE
genotype on the levels of TC, LDL-C, and apoB, with values
increasing progressively in individuals with 2/3, 3/3, and 3/4
genotypes.21 22 23 24 25 26
The percentage of sample variance attributable to common apoE
polymorphism was remarkably similar between studies done in 3
different pediatric populations: white Americans, Italians, and French
Canadians. It ranged from 4.5% to 5.9%, 5.6% to 7.4%, and 6.0% to
8.2% for TC, LDL-C, and apoB concentrations,
respectively.21 22
Conflicting results have been reported regarding the association of the apoB signal peptide length polymorphism with variation in lipid and apoB concentrations in adults. Some found an association between the Del allele and increased concentrations of TC, LDL-C, and apoB,9 27 28 29 while others did not detect this effect.9 30 Only 1 study is available for adults with FH, and no association was found between apoB Ins/Del genotypes and lipid levels.17 This observation is similar to our results in children with FH. However, we detected an effect of this polymorphism on mean LDL-C and apoB concentrations and on the mean TC to HDL-C ratio in controls. Sample size considerations do not seem to solely explain the discrepancies noted between the apoB genotype effect observed in controls compared with that observed in cases, as no trend could be seen in FH subjects. The reduced clearance of apoB-containing particles in FH may offset a modest effect on apoB secretion associated with apoB signal peptide polymorphism.
Our most unexpected result was the finding of a strong interaction between apoE and apoB Ins/Del genotypes on control apoB concentrations and the TC to HDL-C ratio, to the extent that no significant effect of the apoE genotype could be detected in those carrying the Ins/Ins genotype. Obviously, this result will need to be reproduced in other studies. However, a recent study showed that the apoB signal peptide and apoE genotypes interact to modulate hepatic secretion of VLDL.31
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Acknowledgments |
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This work was supported in part by grants from the Fondation de l’Hôpital Sainte-Justine and the Fonds de la Recherche en Santé du Québec (Réseau FRSQ/Hydro-Québec). N.B. was supported by a fellowship from the Department of Pediatrics, University of Montreal, Quebec, Canada, and by a fellowship from the Hoffmann–La Roche Foundation, Switzerland. The authors wish to thank Marie-Claude Guertin, PhD, for statistical analyses.
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Footnotes |
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Reprint requests to Marie Lambert, MD, Medical Genetics Service, Sainte-Justine Hospital, 3175 Côte Ste-Catherine, Montreal (Qc) H3T 1C5, Canada.
Received February 22, 2001; accepted March 8, 2001.
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