© 1995 American Heart Association, Inc.
Articles |
Determinants of Lipid Levels Among Children With Heterozygous Familial Hypercholesterolemia in Norway
From the Lipid Clinic, Medical Department A, National Hospital (S.T., M.S., L.O.), and the Department of Medical Genetics, Ullevål University Hospital (T.P.L.), Oslo, Norway.
Correspondence to S. Tonstad, MD, MPH, Lipid Clinic, Rikshospitalet, N-0027 Oslo, Norway.
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Abstract |
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Abstract Three founder mutations have been discovered among individuals with familial hypercholesterolemia (FH) in Norway: FHElverum and FHSvartor, predicted to be null alleles, and FHC210G, predicted to disrupt the secondary structure of the ligand-binding domain. To clarify the effect of these and other mutations on lipid levels and parental history of premature cardiovascular disease, we examined 164 boys and girls ages 6 to 16 years with heterozygous FH. Among all children, serum cholesterol levels of the FH parent, percent body fat, pubertal stage, and serum cholesterol levels of the non-FH parent, but not apo E polymorphism, were significant determinants of LDL cholesterol levels in a stepwise multiple regression equation and explained 40% (95% confidence interval [CI], 25% to 55%) of the variance in LDL cholesterol. Among boys, percent body fat, dietary sucrose, and apo E genotype determined 31% (95% CI, 14% to 49%) of the variance in triglyceride levels; whereas among girls, only percent body fat was associated with triglyceride levels. Percent body fat was not associated with LDL cholesterol or triglyceride levels in the FHC210G group. The children's and FH parents' lipid levels and premature cardiovascular disease among parents were similar among the null-allele and defective-protein groups and in those with an undetected mutation. These data confirm that the phenotypic expression of FH in childhood is influenced by modifiable lifestyle characteristics and by genetic factors other than the underlying mutation and raise the possibility that body fatness may interact with genotype in determining lipid levels.
Key Words: familial hypercholesterolemia • LDL receptor mutation • apo E • dietary intake, children
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Introduction |
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Among children with heterozygous FH, elevated LDL cholesterol levels are due to a mutation in the LDL receptor gene. Measures to prevent cardiovascular disease are recommended early in life.1 2 However, it is not clear to what extent lipid levels among these children may be influenced by environmental factors, by variability in the underlying mutation, or by other genetic factors. Among adults, the outcome of the disorder may be influenced by the type of LDL receptor mutation as well as by sex, age, hypertension, smoking, and levels of triglycerides, HDL cholesterol, and Lp(a).3 4 5 6
Body fatness and dietary fat are well-established determinants of LDL cholesterol, HDL cholesterol, and triglyceride levels.7 8 9 10 11 12 Increased triglyceride levels were found in boys from populations with a high carbohydrate intake.13 At puberty, HDL cholesterol levels decrease among boys but not among girls, whereas total and LDL cholesterol levels decrease in both sexes.14 15 Genotypes of apo E contribute to the variability in lipid levels from infancy and onwards.16 17 18 In older children, alcohol and smoking habits influence lipid levels to the extent observed among adults or more.19 20
Recently, three new founder mutations have been discovered in individuals with FH in Norway.21 22 FHElverum is a point mutation in the first nucleotide of intron 3 of the LDL receptor gene that is predicted to prevent the splicing of intron 3 from mRNA. FHSvartor is a point mutation that creates a stop codon at codon 78 in exon 3. Both mutations are predicted to cause a null allele, and homozygotes for FHElverum are receptor-negative.21 Another mutation, FHCincinnati-5,23 that is also predicted to cause a null allele is found in Norwegians, but it is not a founder mutation. The third founder mutation, FHC210G, is a point mutation in exon 4 that replaces a cysteine residue with glycine. This mutation occurs in repeat 5 of the ligand-binding domain, is considered essential for binding of apo B and E, and disrupts a disulfide bond and the secondary structure of the ligand-binding domain. We compared lipid levels and the family history of premature cardiovascular disease in children with FHC210G, null alleles, or no detected mutation, while taking into account parental lipid levels, apo E polymorphism, and anthropometric and dietary characteristics.
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Methods |
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Subjects
The children were either referred to the lipid clinic or identified through screening of families with known FH. Eligibility was restricted to boys and girls ages 6 to 16 years who completed a medical evaluation and participated in two or more dietary instruction sessions. If the LDL receptor mutation was not detected, FH was diagnosed if the child had one previous total cholesterol level >6.7 mmol/L and if one or both parents had tendon xanthomas and/or total cholesterol levels
7.8 mmol/L with
triglyceride levels <3.0 mmol/L prior to treatment with
lipid-lowering drugs. The study was approved by the regional ethics
review committee. Informed consent was obtained from one or both
parents. Among 202 potentially eligible children, 3 refused the blood test, 3 had chronic illness (homozygous homocystinuria, severe asthma bronchiale, and rheumatoid arthritis), 5 required excessive traveling time, 11 were taking a bile acid sequestrant, and 16 did not agree to participate or did not come to the appointment. The remaining 92 boys and 72 girls were from 121 families not known to be related and represented 141 nuclear families.
Height and weight were measured by the same investigator while the child wore only underwear. Height was measured using a stadiometer to the nearest 0.1 cm. Two measures were obtained, and a third was taken if the first two were more than 0.4 cm apart. The average of the two or the closest two of three measurements were used. Weight was measured to the nearest 0.1 kg. Sexual maturation was scored from 1 (prepubescence) to 5 (full development) according to Tanner.24 Replicate measurements of skinfold thickness were obtained at the triceps and subscapular sites by using Harpenden calipers. Mean values were used for analysis. The percent body fat was calculated from the sex-specific regression equation involving age and the sum of triceps and subscapular skinfolds.11
Dietary instruction followed the guidelines of the National
Cholesterol Education Program.2 Caloric
restriction for obese children (weight >97.5th percentile for height)
was encouraged, but no specific weight-loss plans were implemented. The
dietitian recorded an unexpected 24-hour dietary recall at the
clinic visit. Subjects completed a 4-day weighed dietary record,
including 3 weekdays and a Saturday or Sunday. Children 12 years old
were asked about smoking habits in the absence of their parents. Use of
alcohol was recorded from the Child's Self-Report questionnaire,
completed by all children 11 years old.25 Parental
educational level was recorded as follows: grade 9 (59% of
mothers, 50% of fathers), secondary school (15% of mothers, 13% of
fathers), and university (26% of mothers and 37% of fathers).
Parental history of cardiovascular disease was based on hospital or physician reports of the presence of typical exercise-induced angina pectoris, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, sudden death, or cerebral infarction. Parental lipid levels before treatment with lipid-lowering drugs were obtained from the clinic charts. When available, the mean of two measurements was recorded. Pretreatment HDL cholesterol levels were missing for 38 FH parents, and triglyceride levels were missing for 34. History of cardiovascular disease before 55 years (men) and before 60 years (women) in second-degree relatives was based on family report in most instances.
Laboratory Determinations
Blood was obtained by venipuncture following an 8-
to 10-hour overnight fast. Total cholesterol and
triglyceride levels were determined by enzymatic methods.
HDL cholesterol was determined after precipitation by
heparin/MnCl2. LDL cholesterol was calculated
by the Friedewald formula. No triglyceride levels were
>2.6 mmol/L.
Apo E genotyping was performed using a modification of the method developed by Hixon and Vernier,26 as described by Eiklid and Leren,27 among participants and a group of normolipidemic volunteers. Polymerase chain reaction–based methods were used to identify mutations in the LDL receptor gene. FHElverum and FHSvartor were identified as described by Leren et al.21 FHC210G and FHCincinnati-5 were identified by amplification-created restriction-site assays.22 The presence of the apo B–3500 mutation was determined by the assay of Hansen et al.28
Statistical Analysis
ANOVA was used to compare continuous variables followed by
Scheffé's test for post hoc comparisons. Apo 
allele
frequencies were estimated by gene counting. For comparison of the
distribution of apo E genotypes, one individual from each group
of related children was randomly chosen (n=121). For comparison of
lipid levels among the apo E genotype and LDL receptor
mutation groups, one child was randomly chosen from each group of
siblings and first cousins (n=130). Apo E2 carried the E2/2 or E3/2
genotype, apo E3 carried the E3/3 genotype, and apo E4
carried the apo E4/3 or E4/4 genotype. ANCOVA was used to
determine whether the mean values of lipid levels were similar among
the groups. Pubertal stage and percent body fat were included as
covariates.
Univariate regression coefficients were calculated (all children), followed by a stepwise multiple regression analysis to identify independent determinants of lipid levels. One randomly chosen sibling from each pair of siblings entered the multiple regression. Statistical analyses were performed using the STATVIEW II (Abacus Concepts, Inc) and STATISTICA 4.1 packages on a Macintosh desktop computer.
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Results |
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Demographic and Clinical Characteristics
The mean age ±SD for both sexes was 10±3 years. Two girls and one boy were cigarette smokers. None used alcoholic beverages regularly. Weight for height was above the 97.5th percentile for 8 boys and 4 girls. All but 22 children (13%) lived with the parent who had FH (11 due to death of the parent and 11 due to divorce). The parent with FH was 40±5 years old at the time of the study or at death. Serum total cholesterol levels were higher in the FH parent compared with the non-FH parent (10.2±1.9 versus 5.4±0.9 mmol/L), HDL cholesterol levels were lower (1.2±0.3 versus 1.4±0.4), and triglyceride levels were similar (1.2±0.6 versus 1.1±0.6). Children's total and LDL cholesterol levels were related to the FH parent's total cholesterol levels (r=.42, P=.0001) and weakly with the non-FH parent's levels (r=.16, P=.08) but not with parental educational level.
Lipid Levels in Relation to Pubertal Stage and Body
Fatness
Total cholesterol levels were lower among both boys
and girls at pubertal stages 3 to 5 compared with stages 1 and 2,
although the difference was only significant for boys
(P<.0001 for the overall ANOVA; Table 1
).
LDL and HDL cholesterol levels were lower among the older
boys (P<.0001). The total-to-HDL cholesterol
ratio was similar in all groups.
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LDL cholesterol and triglyceride levels
increased with increasing percent body fat (r=.37 and
r=.40, respectively, for boys [P<.001] and
r=.33 and r=.28 for girls [P<.05]).
In children with the FHC210G mutation, LDL
cholesterol and triglyceride levels did not
correlate with body fat (r=.08 and r=.00,
respectively), whereas the associations were significant in the groups
with null alleles and undetected mutations (Fig 1, a through
c).
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Dietary Characteristics
The dietary records showed that the boys ate more, but the
proportions of energy from major nutrients and from saturated (
9% of
energy), monounsaturated (8% of energy), and
polyunsaturated (6%) fat were similar among girls and boys. The mean
intake of total fat and cholesterol was within the
recommended intake (25% of energy from fat and 84 mg
cholesterol/1000 kcal per day), but sucrose intake was high
(13% to 14% of energy). Among boys, LDL cholesterol
levels correlated with 24-hour-recall cholesterol intake
(r=.21, P=.04), and triglyceride
levels correlated with 24-hour-recall sucrose intake (r=.31,
P=.004). Lipid levels did not correlate with dietary intake
calculated from the weighed record.
Apo E Genotypes and Mutations in the LDL Receptor
Gene
The distribution of apo E genotypes was similar among the
entire group when compared with the unrelated group and was not
significantly different from a normolipidemic group of control subjects
(Table 2). No significant differences were seen in the
raw or adjusted levels of lipids according to apo E group (Fig 2) or when the analysis was performed for each
sex separately.
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A mutation in the LDL receptor gene was found among 66% of unrelated
families. The most common ones were FHElverum (31%),
FHC210G (13%), FHSvartor (10%), and
FHCincinnati-5 (3%). One to three families carried each of
three previously described mutations (FHGujerat,
FHCincinnati-2, and
FHPadova).23 One family carried the apo
B–3500 mutation. These families were not included in the
analysis in Table 3, which shows that lipid
levels of FH children and parents were similar among those with a null
allele, a defective protein mutation, and an undetected mutation.
The distribution of apo E genotype, percent body fat, and
pubertal stage was similar in the groups.
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Twenty-one percent of FH parents had premature
cardiovascular disease. The proportion did not differ
according to the mutation (Table 3
). Significantly more children with
FHElverum than with the other mutations had a second-degree
relative with disease (68% versus 47% for FHC210G,
29% for FHSvartor, 25% for
FHCincinnati-5, and 43% for undetected mutations;
P=.04). However, when parents and second-degree relatives
were coalesced into the same group, the prevalence of disease between
the mutation groups did not differ.
Multiple Regression Analysis
In a stepwise multiple regression equation controlling for sex,
apo E genotype, and cholesterol intake, LDL
cholesterol levels were significantly related to the FH
parent's cholesterol levels, percent body fat, pubertal
stage, and the non-FH parent's cholesterol level
(r=.63, P<.01), which together explained 40%
(R2; 95% CI, 25% to 55%) of the variance in
LDL cholesterol.
Among boys, triglyceride levels were related to percent body fat, percent of dietary energy from sucrose, and apo E genotype (inversely with the latter; r=.56, P<.01), together explaining 31% (95% CI, 14% to 49%) of the variance in triglyceride levels. Among girls, only percent body fat was related to triglyceride levels, explaining 7% (95% CI, 0.2% to 27%) of the variance.
HDL cholesterol was related to percent body fat in the apo E2 group (r=-.62) but not in the other apo E groups (r=-.09 to r=.02); however, the group was too small for a separate multivariate equation. HDL cholesterol was related to the FH parent's HDL cholesterol and to pubertal stage (r=.42), explaining 17% (95% CI, 6% to 31%) of the variance in HDL cholesterol levels.
Characteristics of Nonparticipants
Nonparticipating children (19 boys and 19 girls) were older
(12.8±2.6 years), but their lipid levels were similar to those of an
age-matched, randomly selected group of participating children (data
not shown). The FHElverum mutation was found among 5
(24%). Two had a parent with cardiovascular disease,
and 57% reported a second-degree relative with premature disease.
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Discussion |
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Evidence from Finland indicates that diet may be more important than genetics in determining lipid levels in normolipidemic children.29 In this study, parental cholesterol levels, body fatness, and diet influenced lipid levels in children with FH rather than the type of underlying mutation, suggesting that modifiable lifestyle factors remain important, even in the presence of severe elevations of LDL cholesterol.
The comparison of the mutations appears to be valid, as nonparticipants
had family histories and lipid levels similar to those of participants.
Both relatively low (6.3 mmol/L) and very high (11.0 mmol/L) total
cholesterol levels were observed within each founder
mutation group. Whether the mutation created a stop codon, affected
mRNA splicing, or disrupted the secondary structure of the
ligand-binding domain did not affect lipid levels, and premature
cardiovascular disease was equally prevalent in all
groups. Other mutations that disrupt disulfide bonds, such as
FHC176F and FHC176Y, have previously
been shown to result in a receptor-negative
phenotype23 ; thus, it is not surprising that
FHC210G had equally deleterious effects on lipid levels as
the mutations expected to cause null alleles. The range of LDL
receptor activity in a group of the heterozygous parents was similar
regardless of the specific mutation that was
present.30 These data confirm findings from FH
patients in London with different mutations than the ones detected in
this study but that also show that phenotypes resulting from
null alleles and from mutations in repeat 5 were
similar.6
In children the duration of the environmental impact on lipid levels is short but may be marked.20 The effect of obesity was as notable or more so than observations in population-based studies.7 8 9 10 11 We are not aware of comparable reports among children with FH. In contrast to findings in normolipidemic children, HDL cholesterol was inversely related to body fatness only in the apo E2 group.31 Although apo E genotype may modulate the association between body fatness and lipid levels, we are not aware of previous data indicating that the LDL receptor mutation may interact with obesity. Among those with FHC210G, body fatness did not appear to affect LDL cholesterol and triglyceride levels. The explanation for this observation, which will need to be confirmed, is unknown. Binding of VLDL to the receptor would be expected to be impaired in persons carrying this mutation.6
Cholesterol levels decrease at puberty, but the differences between the pubertal stages were greater than expected.14 15 Young children may require higher levels of serum cholesterol for referral to the clinic than older children. Referral bias may also explain higher serum cholesterol values among girls than boys in this study. In a previous study among FH adults treated at a lipid clinic, cholesterol levels were higher in women than in men.3 But among adults identified through an ongoing screening of hypercholesterolemic individuals, cholesterol levels were not higher among women.5
Dietary intake based on a weighed-food record is liable to bias, as respondents may report a lower caloric intake and more healthful foods than usual.32 33 34 While a 24-hour recall does not describe the usual diet, the information obtained from a recall is more accurate, particularly the first time that a recall is obtained,34 as was the case in this study. The intake of sucrose was high (14% of total energy) compared with recommendations (10% of total energy),35 indicating that children substitute sucrose for fat when following a low-fat diet, as noted in a report of free-living children,36 and resulting in increased triglyceride levels in some children.
The impact of parental cholesterol levels on those of their offspring may be due to a shared environment, to the presence of a common mutation, and to many other genetic factors, including apo B and apo E polymorphisms and levels of lipid-regulating enzymes. We did not assess apo B polymorphisms, which have been shown to influence the variability of LDL cholesterol among normolipidemic Finnish children.15 37 Correlations between parental and child levels persist beyond the period of shared environment38 ; thus, the small group of children that did not live with the FH parent was included in the analyses. Total cholesterol levels were higher among FH parents compared with those of their children, reflecting the effects of age and possibly early dietary intervention among the children.
The presence of apo E genotypes did not affect the level of LDL cholesterol. This is similar to results seen in some, but not all, FH-based studies in Canada, Japan, and Finland.3 39 40 41 Varying findings may reflect differences in the genetic background of the various populations or in the heterogeneity of the LDL receptor gene mutations. It has been suggested that the effect of the LDL receptor mutation overwhelms the effect of apo E alleles.3 Some studies,40 including this one, may lack sufficient power to show differences. The relationship between apo E genotype and lipids is established among normolipidemic boys but remains unclear among girls and postmenopausal women.17 18 We found that among boys triglyceride levels were higher in the apo E2 group, after adjustment for body fatness and diet, confirming findings among adults with FH.3
The presence of severe elevations of LDL cholesterol due to FH does not preclude the effect of environmental and other genetic influences on lipid levels starting in childhood, although childhood may provide relatively unobscured data on the impact of genotype. Further work is needed to elucidate the interaction between the type of LDL receptor mutation and these influences.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Stein Evensen for critical comments.
Received February 27, 1995; accepted May 18, 1995.
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C. M. Hutter, M. A. Austin, and S. E. Humphries Familial Hypercholesterolemia, Peripheral Arterial Disease, and Stroke: A HuGE Minireview Am. J. Epidemiol., September 1, 2004; 160(5): 430 - 435. [Abstract] [Full Text] [PDF]
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U.-M. Koivisto, H. Gylling, T. A. Miettinen, and K. Kontula Familial Moderate Hypercholesterolemia Caused by Asp235->Glu Mutation of the LDL Receptor Gene and Co-occurrence of a De Novo Deletion of the LDL Receptor Gene in the Same Family Arterioscler. Thromb. Vasc. Biol., July 1, 1997; 17(7): 1392 - 1399. [Abstract] [Full Text]
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S. N. Pimstone, J. C. Defesche, S. M. Clee, H. D. Bakker, M. R. Hayden, and J. J.P. Kastelein Differences in the Phenotype Between Children With Familial Defective Apolipoprotein B-100 and Familial Hypercholesterolemia Arterioscler. Thromb. Vasc. Biol., May 1, 1997; 17(5): 826 - 833. [Abstract] [Full Text]
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S. Tonstad, O. Joakimsen, E. Stensland-Bugge, T. P. Leren, L. Ose, D. Russell, and K. H. Bonaa Risk Factors Related to Carotid Intima-Media Thickness and Plaque in Children With Familial Hypercholesterolemia and Control Subjects Arterioscler. Thromb. Vasc. Biol., August 1, 1996; 16(8): 984 - 991. [Abstract] [Full Text]
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