© 1998 American Heart Association, Inc.
Original Contributions |
Haplotypes of the ApoA-I/C-III/A-IV Gene Cluster and Familial Combined Hyperlipidemia
From the Department of Biochemistry, National Public Health Institute, Helsinki (E.T., S.N., L.I., C.E.); the Department of Human Molecular Genetics, National Public Health Institute, Helsinki (P.P., L.P.); the Department of Medicine, Helsinki University Central Hospital, Helsinki (K.P., M.-R.T.); and the Department of Medicine, University of Turku, Turku (I.N.), Finland.
Correspondence to Christian Ehnholm, Department of Biochemistry, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail Christian.Ehnholm{at}ktl.fi
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Abstract—Familial combined hyperlipidemia (FCHL) is the most frequent familial lipoprotein disorder associated with premature coronary heart disease. However, no genetic defect(s) underlying FCHL has been identified. A linkage between FCHL and the apoA-I/C-III/A-IV gene cluster has been reported but not verified in other populations. A recent study identified FCHL susceptibility haplotypes at this gene cluster. To study whether such haplotypes are also associated with FCHL susceptibility in Finns, we studied 600 well-defined Finnish FCHL patients and their relatives belonging to 28 extended FCHL families by using haplotype, linkage, sib-pair, and linkage disequilibrium analyses. The genotypes of the MspI polymorphisms were associated with total serum cholesterol (P<0.01) and apoB (P<0.05) levels in spouses, which represent the general Finnish population. However, no evidence of direct involvement of any of these loci or their specific haplotypes in the expression of FCHL in the Finnish FCHL families was found.
Key Words: apoA-I • apoC-III • apoA-IV • familial combined hyperlipidemia • coronary heart disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Familial combined hyperlipidemia (FCHL), originally described by 3 independent groups,1 2 3 is characterized by an elevation of cholesterol and/or triglyceride levels. In Western societies, the condition is found in 1% to 2% of the population and in
10% of survivors of
myocardial infarction, designating FCHL as one of the most frequent
familial dyslipidemias associated with premature
coronary heart disease (CHD). In affected subjects, a common
characteristic is an increase in small, dense LDL
particles.4 5 6 A consistent
metabolic finding in FCHL is an increased apoB plasma
level,7 8 which is due to either increased
production or lowered clearance of apoB-containing
lipoproteins.9 10 11 Association between the apoA-I/C-III/A-IV gene cluster on chromosome 11 and FCHL has been the subject of several studies. An association between FCHL and an XmnI restriction fragment polymorphism in the 5'-flanking region of the apoA-I gene was reported,12 and the finding was later confirmed by linkage (logarithm of the odds [lod] score, 6.86) without recombinants in 7 families.13 Further evidence for an association between this gene cluster and FCHL has been provided by other groups,14 15 16 but the findings have also been challenged,17 18 19 20 and the positive linkage result has not been confirmed. An explanation for this controversy may be provided by a recent study,21 in which the contribution of the apoA-I/C-III/A-IV gene cluster is presented as an epistatic interaction between different haplotypes, a finding that may also partially explain the paradigm of the complex and varying phenotypes of FCHL. A specific combination of haplotypes (1-1-2/2-2-1, "the high-risk haplotype combination") derived from polymorphic XmnI and MspI sites in the 5'-flanking region of the apoA-I gene and the SstI site in the 3'-untranslated region of the apoC-III gene was reported to be more frequent in hyperlipidemic patients (frequency, 0.06) than in normolipidemic relatives (frequency, 0.03, P<0.05) or spouses (frequency, 0.005, P=0.01). The aim of the current study was to test whether these specific haplotypes are also associated with FCHL in Finnish FCHL families.
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Methods |
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Study Subjects
The collection of carefully documented pedigrees with several affected individuals has been reported.22 The study design was approved by the ethics committees of the participating centers, and each subject gave informed consent before participation in the study. A total of 28 pedigrees with 600 subjects were included in the study in 3 phases. In the first phase, probands fulfilling the following criteria were selected from hospital records: age 30 to 55 years for men and 30 to 65 years for women; at least a 50% stenosis in 1 or more coronary arteries confirmed by coronary angiography; and serum total cholesterol and/or serum triglycerides higher or equal to that of the age- and sex-specific 90th percentile. Exclusion criteria for the proband were type I diabetes, hypothyreosis, and hepatic or renal disease. In the second phase, the proband and all first-degree relatives were examined. Families with several affected individuals and at least 2 different lipid phenotypes, of which 1 was the combined lipid phenotype IIB in the proband or his/her first-degree relative, were included in the third phase, for which all accessible relatives and their spouses were examined. The characteristics of the study population are shown in Table 1
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Biochemical Analyses
The biochemical analyses and baseline data have been
described in detail.22 In short, for each family
member over the age of 5, blood was drawn after an overnight fast for
the measurement of serum lipids and DNA isolation. Subjects using
lipid-lowering agents were asked to interrupt their medication for 4
weeks before blood sampling. Serum samples were stored frozen at
-70°C until analyzed. Serum total cholesterol
and triglycerides were determined with automated enzymatic
methods.23 HDL cholesterol was
determined as described.24 Familial
hypercholesterolemia was excluded from each
pedigree by determining the LDL receptor status of the proband by using
the lymphocyte culture method.25 None of the
study subjects had tendon xanthomas.
Genotyping
DNA was isolated by a phenol-chloroform extraction
method.26 Three polymorphisms,
XmnI,27
MspI,28 and
SstI,29 at nucleotide
positions -2500C/T and -78G/A of the apoA-I gene and at 3175G/C of
the apoC-III gene, were determined. In the solid-phase minisequencing
method used,30 variable
nucleotides are identified by a single
nucleotide primer extension reaction catalyzed by DNA
polymerase from a polymerase chain reaction (PCR) product on a
solid support. Three different primers were used to study each
polymorphism: each DNA fragment, containing a
nucleotide to be tested, was first amplified by PCR by
using a pair of primers, and then the product was analyzed
by a detection primer required for minisequencing. The primers that
were used to amplify the target sequence were the same as those used
previously21 for MspI and
SstI polymorphisms, but for polymorphism
XmnI, we used primers 5'-AGCCACCAAACAGTCCAACC-3' and
5'-TCAGGGACTTCTCAGTTTCC-3', which are located closer to the
XmnI site. The detection primers were
5'-ATCAGCTCTGTCCAGAAAGAC-3', 5'-AGTGAGCAGCAACAGGGCC-3', and
5'-ATTGCAGGACCC-AAGGAGCT-3' for XmnI, MspI,
and SstI polymorphisms, respectively. The alleles
were coded so that allele 1 refers to an absence of restriction
site with the XmnI and SstI polymorphisms but
the presence of the restriction site with the MspI
polymorphism.21 With this coding scheme,
allele 1 was found to be the most common allele for all
polymorphisms.
Linkage and Sib-Pair Analyses
The linkage analyses were computed by using
LINKAGE31 32 and
FASTLINK31 33 34 35 program versions
5.1 and 2.3, respectively. The possible
heterogeneity of FCHL was tested, and an affected
sib-pair study on nuclear families was done by the programs
HOMOG and SIBPAIR.32 36
The linkage analyses were calculated by using both a dominant
and a recessive mode of inheritance. Based on the estimated FCHL
prevalence, population gene frequencies of 0.004 and 0.089 for the
dominant and recessive models, respectively, were used. Frequency of
phenocopies was estimated to be 0.005, and penetrance, 0.90 in the
calculations. To determine individuals status, the age- and
sex-specific 90th percentiles of lipids derived from
FINMONICA, a large population-based survey done in
1992,37 were used for both probands and family
members. The fractile cut points for subjects under the age of 25 were
derived from the Cardiovascular Risk Factors in Young
Finns study.38 To reduce problems caused by
unknown penetrance, subjects were coded as affected in linkage,
sib-pair, haplotype relative risk (HRR), and tests of transmission
disequilibrium (TDT) analyses if they had
cholesterol and/or triglycerides >90th age-
and sex-specific percentiles; healthy, if they had both
cholesterol and triglycerides <30th age- and
sex-specific lipid percentiles; and unknown, if they had lipid values
between the 30th and 90th age- and sex-specific percentiles. If a
spouse of a family member in the second generation in any of the 28
families was also affected according to the lipid criteria, the
offspring of these couples were not included in the calculations to
avoid bilineal introduction of the trait. Allele frequencies of
0.214, 0.198, and 0.224, which were estimated by random sampling from
families for the less common alleles of Sst I,
MspI, and XmnI polymorphisms, respectively,
were used in the linkage analyses. Power calculations for
linkage analysis were done by using the SLINK
program.39 40 With the use of a dominant model
with linkage parameters given above and a marker with 4
alleles with equal frequencies, the average simulated lod score was
20.30 (
=0.00); for a recessive model, the lod was 11.33
(=0.00).
TDT, HRR, and Linkage Disequilibrium (LD)
TDTs and HRR analyses were done through
ANALYZE, an accessory program to the
LINKAGE package, which simplifies the use of programs
TDTLIKE and HRRLAMB for this
purpose.41 42 The HRRLAMB program
selects the first affected individual from each pedigree for which both
parents are typed and then tests the nonrandom
segregation41 of the transmitted and
untransmitted alleles by a likelihood ratio
test.42 The likelihood ratio–based
TDT42 considers all the alleles jointly and
tests whether 1 of them is transmitted from heterozygous parents
preferentially to affected offspring. LD analyses between
polymorphisms were estimated by a permutation
procedure,43 and Hardy-Weinberg equilibrium of
genotypes and haplotypes was tested by an exact
test44 ; both methods are part of the program
package ARLEQUIN.45 Haplotypes were
determined by combining the use of haplotype estimation algorithms of
the GENEHUNTER program package,46
version 1.0, and inspection of the pedigrees. The nonrandom
distribution of alleles between probands and spouses was tested by
Fisher's exact test; the distribution of genotypes and
haplotypes by 
2 test; and haplotype
combinations by an exact test analogous to Fisher's exact test
extended to a 2xk contingency table, where k is
the number of haplotype combinations.47
Logistic Regression Analyses and ANOVAs
To study the effects of specific haplotype combinations in the
pedigrees, we used logistic regression modeling and variance
analysis. Subjects were coded as hyperlipidemic
if they had cholesterol and/or triglycerides
>90th age- and sex-specific percentiles. Triglyceride
values were logarithmically transformed (base e) in all
analyses. The regression analyses and ANOVAs were done
with the Statistical Package for the Social Sciences (SPSS Inc),
version 6.1.3. In the logistic regression analysis, the
association of the haplotype combinations with FCHL phenotype
was tested after adjusting for sibship. Two alternative models were
tested for each haplotype combination and for all haplotype
combinations together: a model in which only the sibship was known for
each individual and a second model in which haplotype combinations were
added in the model. The statistical significance of the comparison
between these 2 models was tested on the basis of the change in log
likelihood. The effects of the haplotype combinations on
triglyceride, cholesterol, and apoB levels were
studied by variance analysis adjusted for sibship, age, sex,
and body mass index. In addition, the contribution of genotypes
of each polymorphism and of haplotype combinations on serum total
cholesterol, triglyceride, and apoB levels was
studied in spouses by ANOVA.
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Results |
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Linkage and Sib-Pair Analyses
The results of 2-point linkage analyses between FCHL phenotype and the polymorphisms remained nonsignificant with the use of both a dominant and a recessive model. The maximum lod scores of SstI, MspI, and XmnI polymorphisms with the dominant mode of inheritance were 0.00 (0.50), 0.00 (0.50), and 0.29 (0.22), respectively. (The recombination fractions are given in parentheses.) With the recessive model, the maximum lod scores were 0.08 (0.32), 0.00 (0.50), and 0.04 (0.36), with the same order of markers. In multipoint analyses with MLINK, the maximum lod scores were 0.27 (0.30) with a dominant mode of inheritance and 0.29 (0.28) with a recessive model. In the nonparametric affected sib-pair analyses, there was no excess allele sharing detectable. There was no significant heterogeneity detectable by the HOMOG program.
TDT, HRR, and LD Analyses
No significant differences in the frequencies of alleles,
genotypes, haplotypes, or haplotype combinations were observed
between probands and spouses. The frequencies are also given for family
members divided according to hyperlipidemic or
normolipidemic status, although the statistical comparisons between
these latter groups cannot be done by direct comparisons between
frequencies because they do not represent independent study
subjects (Tables 2 and 3). The distribution of single-locus
genotypes, haplotypes, and haplotype combinations did not
differ significantly from Hardy-Weinberg equilibrium determined from
total allele and haplotype frequencies, with 1 exception: in
spouses, the frequencies of haplotypes deviated from those estimated
from allele frequencies (P<0.05). That finding was due
to the fact that 2 polymorphisms, XmnI and
MspI, were in LD (D'=0.52 for rare alleles,
P<0.05). No significant LD between FCHL and any of the
polymorphisms was detected by the HRRLAMB program. The
segregation of these loci did not differ significantly from random in
TDTs.
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Logistic Regression Analyses and ANOVAs
In spouses, the genotypes of the MspI
polymorphism were associated with total cholesterol
(P=0.008) and apoB (P=0.036) levels (Table 4). The total serum
cholesterol level was 5.29 mmol/L in 1/1 homozygotes
(n=91), 5.90 mmol/L in heterozygotes (n=38), and 5.55 in 2/2
homozygotes (n=2). The total serum apoB level was 91.7 mg/100 mL in 1/1
homozygotes (n=91), 104.8 mg/100 mL in heterozygotes (n=39), and 68.0
mg/100 mL in 2/2 homozygotes (n=1). With the XmnI and
SstI polymorphisms, no statistically significant
differences in mean lipid values were detected between
genotypes.
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To analyze whether any haplotype combination could have an
effect on the expression of the FCHL phenotype or lipid values,
all informative sibships (n=199) were tested by logistic regression and
variance analysis. Analyses revealed no dependence
between FCHL, cholesterol, triglyceride, or
apoB levels and the presence of any of the haplotype combinations. When
the sibship of each individual was known, the FCHL status was correctly
predicted, on average, in 61.6% of subjects. When the information for
any single haplotype combination was added, the accuracy of prediction
increased at best by 4%, to a total of 65.6% with the haplotype
combination 1-1-1/1-1-1 (P=not significant) (Table 5). When all the haplotypes were included
in the model in a single step, the accuracy of prediction increased to
67.2%, but the effect was still nonsignificant (P=0.21). No
significant differences in the frequencies of haplotypes or haplotype
combinations were observed between probands and spouses. The
"high-risk haplotype combination" 1-1-2/2-2-1 was observed in both
affected and healthy family members as well as in spouses. It was found
in 3/27 probands and in 2/114 spouses (P=not significant).
In those 2 spouses carrying that haplotype combination, their apoB
levels were 74.0 and 79.3 mg/100 mL, serum total
cholesterol 4.67 and 5.10 mmol/L, and serum total
triglycerides 0.60 and 1.27 mmol/L; all values were
below the mean of those not having that haplotype combination. The
effects of the haplotype combinations on serum total
cholesterol, triglycerides, and apoB were
analyzed in spouses by ANOVA. The mean value of apoB level in
the 2 individuals carrying haplotype combination 1-1-1/2-1-2 was 48.5,
which was lower than the mean of 156 other spouses
(P=0.014), but after correction for multiple testing, that
finding cannot be regarded as statistically significant.
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Discussion |
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Originally based on family inspection, analysis of the number of affected sibs, and the distribution of adjusted lipid values, it was suggested that FCHL constitutes an autosomal dominant trait.1 2 3 Segregation analyses have supported major gene effects on triglyceride levels, apoB levels, and LDL particle size distribution in affected families.48 49 The dominant model of inheritance is supported by a recent finding of linkage50 to chromosome 1q21-q23 in Finnish pedigrees. The linkage of a syntenic locus with FCHL has also been shown in a mutant mouse strain.51 Although this finding of linkage seems now very important, it has been noted several times in the course of research on FCHL that it is heterogeneous and also that in individual families, several genes can be involved in the expression of the FCHL phenotype. It is thus plausible that there are still other gene defects associated with FCHL in Finnish pedigrees. In fact, due to the broad definition of FCHL, defects causing FCHL may be found at any step along the metabolic pathways of apoB-containing lipoproteins; from the synthesis of VLDL and chylomicrons to the clearance of their end products, chylomicron remnants, and LDL from plasma.
Widely studied candidate genes of FCHL include the major genes affecting the metabolism of apoB-containing lipoproteins. The apoB gene locus does not contribute significantly to the development of FCHL, but whether the genes regulating its expression might contribute to the FCHL phenotype is not known.52 Mutations in the lipoprotein lipase gene and reduced postheparin plasma lipoprotein lipase activity have been found in FCHL patients in some studies53 54 55 but not in all.17 The LDL receptor would be an obvious candidate gene for FCHL, but its defects cause a different phenotype and disease.56 57 Despite this, another still-unknown gene in close proximity to the LDL receptor gene may be associated with the small, dense LDL phenotype.58 Likewise, lipoprotein modulators like cholesterol ester transfer protein,59 60 lipoprotein(a),61 hormone-sensitive lipase,62 and hepatic lipase63 are potential candidates. In Finnish FCHL families, there was no evidence of linkage between FCHL and lipolytic enzymes.64 Defects in the insulin signaling pathway65 or in an even more potent adipsin acylation stimulating protein signaling pathway are intensively studied candidate genes for FCHL. Adipsin acylation stimulating protein, also called basic protein I, is a fragment of the third component of plasma complement (C3a-des-Arg) and a strong modulator of triglyceride synthesis in adipocytes.66 Other cellular candidate genes include basic protein II, which affects cholesterol ester formation in the liver,67 and microsomal triglyceride transfer protein, which catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces.68 One of the most important candidate loci of FCHL, and also the subject of the current study, is the apoA-I/C-III/A-IV gene cluster on chromosome 11. Taking into consideration previous partially contradictory results and the recent findings of complex genetic contribution of specific haplotypes, we considered it important to test the involvement of the apoA-I/C-III/A-IV gene cluster in the expression of the FCHL phenotype in Finns.
We found that in spouses, representing the control group,
the MspI polymorphism in the promoter region of the
apoA-I gene was associated with total cholesterol and apoB
levels. The MspI polymorphism had earlier been
associated with elevated HDL
cholesterol,28
apoA-I,69
triglyceride,16 and apoB
levels.16 We could also confirm the positive LD
between MspI and SstI
polymorphisms.70 The G
A
nucleotide change that creates the MspI
polymorphism has been reported to increase the transcription
efficiency of apoA-I, probably by reducing the affinity of a regulatory
factor.71
We found the specific combination of haplotypes, which has previously been reported to be associated with FCHL status and plasma cholesterol and triglyceride values, in 11% of the probands and in 2% of their spouses, but the result was not statistically significant. None of the further analyses supported the association of any haplotype combination with the FCHL phenotype or lipid levels. There was no linkage between the studied markers and the FCHL phenotype. Because linkage analysis is dependent on the inheritance model used, several "model-free" statistical tests were performed, including nonparametric affected sib-pair, TDT, HRR, LD, logistic regression, and ANOVA. There was no excess allele sharing, allelic association, or LD between the studied polymorphisms and the FCHL phenotype. There was no statistically significant TD or increased HRR detectable.
The fact that the studied polymorphisms showed no statistically significant association with the FCHL phenotype in Finnish FCHL families does not rule out that there could be other important polymorphisms in these genes that may be in LD with these polymorphisms in other populations. Other possible explanations for the difference between the results of the current study and earlier positive findings can probably be found in different family selection, different criteria used for the determination of the FCHL affected status, different population gene frequencies, and partially the use of different statistical approaches.
In the study of Dallinga-Thie and coworkers,21 wherein the complex genetic contribution of the apoA-I/C-III/A-IV gene cluster to FCHL was presented, association studies were done with all normolipidemic and hyperlipidemic individuals in the FCHL families without adjusting for sibships. In that study, the individuals in the hyperlipidemic group were related and did not represent independent individuals, as is usually required in association analyses.72 In the hyperlipidemic relatives of that study, the rare alleles of XmnI and MspI polymorphisms were more frequent than in our study (a proper statistical comparison would require independent sampling). Also, the frequencies of haplotype combinations were clearly different between these 2 studies. The frequency of the most common haplotype combination, 1-1-1/1-1-1, was much lower in the Finnish FCHL family members than in the Dutch, and concurrently some haplotype combinations, ie, 1-1-1/1-2-2, 1-1-1/2-1-1, 1-1-1/2-1-2, 1-1-1/2-2-2, 1-1-2/1-2-1, 1-1-2/2-1-2, 1-2-1/2-1-1, 1-2-1/2-2-2, 2-1-1/2-2-2, and 2-2-1/2-2-2, were not encountered in the Dutch FCHL families. Two haplotype combinations, 2-1-1/2-2-1 and 1-2-1/1-2-1, were not seen in Finnish FCHL families. Those haplotypes in which the S2 allele combined with the X2 and M2 alleles were rare in Finnish and absent in Dutch FCHL families. The populations show minor differences in haplotype frequencies, but the frequencies of the haplotypes 2-2-2, 1-2-2, and 2-1-2 were also so low in the Finnish population that the different outcome with these rare haplotypes may have occurred by chance. We also used different patient selection (based on age- and sex-specific cutoff values) and different exclusion methods of familial hypercholesterolemia than in the previous study.21
Although we cannot exclude the possibility that the genes of the apoA-I/C-III/A-IV gene cluster act as a minor modifying factor in the pathogenesis of FCHL, we conclude that the current study does not support the direct involvement of these genes in FCHL in the Finnish FCHL families. The current study does not rule out the possibility that there could be functional mutations in other populations that are in LD or show other types of association with the studied polymorphisms.
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Acknowledgments |
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This work was supported by grants from the Academy of Finland (C.E., L.P., M.-R.T.), the Helsinki University Central Hospital Research Foundation (C.E., L.P., M.-R.T.), the Finnish Heart Foundation (C.E., L.P., M.-R.T.), and the Emil Aaltonen's Foundation (I.N., P.P.). We thank the members of Finnish FCHL families participating in the "European Multicenter Study on Familial Dyslipidemias With Premature Coronary Heart Disease" (EUFAM Study). Sirpa Koskela's, Leena Pahlama's, Aira Heine's, and Terho Lehtimäki's work with these families and practical arrangements in family data collection are gratefully acknowledged. We wish to thank Elli Kempas, Sirkka-Liisa Runeberg, Leena Lehikoinen, Ritva Marjanen, Ulla Minkkinen, and Anne Jokiaho for excellent laboratory technical assistance and Aki Suomalainen for maintenance of databases and drawings for this article. We thank Petri Kovanen, Wihuri Research Institute, for LDL receptor status determinations.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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This investigation is a part of the larger EUFAM Study, supported by the European Commission, contract number BMH4-CT96-1678.
EUFAM Study Group
Prof Christian Ehnholm, coordinator, Dr Esa Tahvanainen:
National Public Health Institute, Department of Biochemistry, Helsinki,
Finland; Prof Leena Peltonen, Dr Päivi Pajukanta: National Public
Health Institute, Department of Human Genetics, Helsinki, Finland; Prof
Marja-Riitta Taskinen, Dr Kimmo Porkka, Dr Kati Ylitalo: Department of
Medicine, University of Helsinki, Helsinki, Finland; Assoc Prof Jorma
Viikari, Dr Ilpo Nuotio: Department of Medicine, University of Turku,
Turku, Finland; Prof Markku Laakso, Dr Jussi Pihlajamäki:
Department of Medicine, University of Kuopio, Kuopio, Finland; Prof
Anders G. Olsson: Department of Internal Medicine, Linköping
University, Linköping, Sweden; Prof Ole Færgeman, Dr
Jesper Jensen: Department of Medicine and Cardiology A,
Aarhus Amtssygehus, University Hospital, Aarhus, Denmark; Prof Paolo
Rubba, Dr Paolo Pauciullo: Universitá degli studi di Napoli
Federico II, Il Facoltá di Medicina Interna e Malattie
Dismetaboliche, Naples, Italy; Prof Louis Havekes, Prof
Rune Frants: TNO-PG, Gaubius Laboratory and the Department of Human
Genetics, University of Leiden, Leiden, Netherlands; Prof Gerd
Utermann: Institute of Medical Biology and Human Genetics,
Innsbrück, Austria.
Received January 19, 1998; accepted June 25, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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