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Human Molecular Genetics Pages 331-336  

Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey
Introduction
Results
Discussion
Materials And Methods
   Subjects
   Biochemical analysis
   DNA analysis
   Statistical analysis
Acknowledgements
Abbreviations
References

Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey

Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey

Kimiko Yamakawa-Kobayashi*, Hisako Yanagi1, Hiromi Fukayama, Chiaki Hirano1, Yae Shimakura2, Nao Yamamoto, Tadao Arinami, Shigeru Tsuchiya1 and Hideo Hamaguchi

Department of Medical Genetics, Institute of Basic Medical Sciences, 1Institute of Community Medicine and 2Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan

Received September 23, 1998; Revised and Accepted November 19, 1998

To determine the frequency of familial hypoalphalipoproteinemia in the general population due to mutation of the apolipoprotein A-I (apo A-I) gene, we analyzed sequence variations in the apo A-I gene. The subjects were 67 children with a low high-density lipoprotein (HDL) cholesterol level ([le]38 mg/dl, below the fifth percentile in the population of this study) who were screened from 1254 schoolchildren through a school survey. Four different mutations with deleterious potential, three frameshifts and one splice site mutation, were identified in four of the subjects. The plasma apo A-I levels of the four children with apo A-I gene mutations were reduced to approximately half of the normal levels and were below the first percentile of the general population distribution (80 mg/dl). Thus, the frequency of hypoalphalipoproteinemia due to a mutant apolipoprotein A-I gene was estimated at 6% (95% CI: 2.4-14.4%) in the subjects with low HDL cholesterol levels and 0.3% (95% CI: 0.1-0.8%) in the Japanese population. This suggests that familial hypoalphalipoproteinemia due to apo A-I gene mutations is relatively common.

INTRODUCTION

Many epidemiological and clinical studies have shown that low serum high-density lipoprotein cholesterol (HDL-C) levels are strongly associated with increased risk of coronary heart disease (CHD) (1-7). The protective effect of HDL against atherosclerosis and CHD is thought to be mediated by its involvement in reverse cholesterol transport (8), although several other mechanisms have also been proposed (9,10).

Apolipoprotein A-I (apo A-I) is a single polypeptide chain composed of 243 amino acids in the mature sequence and is the major structural component of HDL. Apo A-I contains eight 22 amino acid repeats between codons 44 and 241 that form amphipathic [alpha]-helices that interact with the lipid surface of lipoprotein particles (6,11,12). Apo A-I is also involved in the esterification of cholesterol as a cofactor for lecithin:cholesterol acyltransferase (LCAT). Thus apo A-I plays a major role in cholesterol efflux from peripheral cells, which is presumably the first step in reverse cholesterol transport (8). Serum levels of apo A-I and HDL-C are strongly correlated (6,13). Several studies have suggested that low levels of apo A-I are a better indicator for CHD than low levels of HDL-C (14,15).

Much of the variation in human HDL-C levels is due to genetic factors. Data from family and twin studies suggest that genetic variation accounts for 40-60% of the interindividual variation in serum HDL-C levels (16-18), although environmental influences, including life style, are also of considerable importance (3,6,19). One cause of low HDL-C levels is familial hypoalphalipo-proteinemia (6,20). Approximately 4% of premature CHD cases have been attributed to familial hypoalphalipoproteinemia (20). It is suggested that in most cases of familial hypoalphalipo-proteinemia, the low HDL-C levels are transmitted as an autosomal dominant trait (6). The apo A-I gene is one of the loci responsible for familial hypoalphalipoproteinemia, and many mutations have been identified in this gene (4,6,11,21-33). Individuals heterozygous for such apo A-I gene mutations have reduced serum HDL-C and apo A-I levels (22-28,30,31,33), and individuals homozygous for the mutations have little or no serum HDL-C and apo A-I (4,6,21,23-28,33).

To assess the impact of the mutant apo A-I genes on low HDL-C levels in the population, we screened for sequence variations in the apo A-I gene of 67 individuals with low HDL-C levels selected from a population of 1254 schoolchildren. Children may be better subjects than adults to assess genetic factors involved in the determination of HDL-C levels because they have less exposure to some environmental factors such as smoking and alcohol.

RESULTS

Table 1 shows the mean values for serum total cholesterol, triglycerides, HDL-C and apo A-I of the 1254 subjects. No significant differences in these values were observed between boys and girls. Figure 1 is a scatter plot between serum HDL-C and apo A-I levels. As expected, a strong correlation was observed between HDL-C and apo A-I levels (r = 0.76, P < 0.001). Among the subjects, 67 children with low HDL-C levels ([le]38 mg/dl, the fifth percentile of HDL-C levels in our subjects) were selected for analysis of sequence variations in the apo A-I gene.


Figure 1. Scatter plot between serum HDL-C and apo A-I levels in 1254 schoolchildren.

Table 1. Lipid and apolipoprotein A-I levels in the 1254 schoolchildren(means ± SD)
  Boys Girls Total
Number 692 562 1254
Age (years) 12.2 ± 1.8 12.1 ± 1.8 12.2 ± 1.8
Total cholesterol (mg/dl) 167.8 ± 26.7 171.0 ± 24.3 169.7± 26.2
Triglyceride (mg/dl) 72.7 ± 34.9 82.7 ± 43.0 77.2 ± 39.1
HDL cholesterol (mg/dl) 54.0 ± 11.6 54.8 ± 10.7 54.4 ± 11.2
Apo A-I (mg/dl) 130.3 ± 19.1 133.3 ± 17.1 131.6 ± 18.3


Using single strand conformation polymorphism (SSCP) analysis and followed by sequencing of DNA amplified from the 67 individuals with low HDL-C levels, we identified mutations in five subjects in the heterozygous state with the wild-type allele (Fig. 2). Three were frameshift mutations. The first frameshift mutation was a single C nucleotide insertion in codons 3-5 where seven consecutive C residues are found. This frameshift mutation was described in our previous report (22). The second mutation was a 4 bp deletion (GGAA) in codons 39 and 40 in exon 3 (Fig. 3A). The third mutation was another 4 bp deletion (AGCT) in codons 224 and 225 in exon 4 (Fig. 3B). The latter two frameshift mutations were novel. The three frameshift mutations described above change the reading frame and create premature stop codons downstream, and truncated protein products are predicted (Fig. 4).


Figure 2. SSCP analysis of the apo A-I gene in children with low HDL-C levels (SS, MM, NH, KK and HK). Band shifts in PCR-amplified DNA fragments are indicated by arrowheads. C, control pattern.


Figure 3. Mutations in the apo A-I gene detected in children with low HDL-C levels. (A and B) Direct sequence analyses from the antisense strand of the 4 bp deletion (GGAA) in codons 39 and 40 (A) and the 4 bp deletion (AGCT) in codons 224 and 225 (B) are shown. The deleted nucleotides are indicated by boxes. In subjects with frameshift mutations; two superimposed sequences derived from normal and mutant alleles are shown after the site of the mutation (arrowhead). The sequence of the other frameshift mutation is reported elsewhere (22). The subject with the 4 bp deletion in codons 39 and 40 has a C for G substitution in codon 38 (A). (C and D) The base substitutions in a splice donor site in intron 2 (C) and in codon 35 (D) are shown. The substitutions are indicated by the arrows and asterisks.


Figure 4. Schematic representation of the positions and natures of the four mutations in the apo A-I gene identified in this population-based survey. Deleted nucleotides are boxed; the inserted nucleotide is underlined.

The fourth mutation was a novel splicing mutation due to a C for G transversion at the 5[prime] splice consensus sequence of intron 2 (Figs 3C and 4). This nucleotide change destroys the splice donor site of intron 2 and results in the generation of aberrant mRNA transcripts. Moreover, two missense mutations were detected. One is a Ser for Gly substitution (GGC->AGC, Gly->Ser) in codon 35 of exon 3 (Fig. 3D) and the other is a Phe for Leu substitution (TTG->TTC, Leu->Phe) in codon 38 (Fig. 3A). The latter missense mutation at codon 38 was detected in the subject with the 4 bp deletion at codons 39 and 40. The three frameshift, one splicing and two missense mutations described above were not observed in the remaining 62 children with low HDL-C levels and in 246 randomly selected normolipidemic children. It is not clear whether the missense mutations cause low HDL-C levels, but it is likely that the missense mutations are not directly related to low HDL-C levels, as described in the Discussion. Therefore, we regarded the three frameshift and one splicing mutations as having deleterious potential. Table 2 presents the serum lipid and apo A-I levels of the four individuals with the frameshift or splicing mutations of apo A-I genes. In addition to HDL-C levels, apo A-I levels were reduced to approximately half the mean value in the general population. The plasma apo A-I and HDL-C levels of the four children with apo A-I gene mutations were below the first and second percentiles, respectively, of the general population distribution (80 and 36 mg/dl, respectively). The subjects’ triglyceride levels were normal.

Table 2. Lipid and apolipoprotein levels in heterozygotes for the mutant apo A-I gene
  Age Mutation HDL-C (mg/dl) Apo A-I (mg/dl) T-Cho (mg/dl) TG (mg/dl)
1 MM 9 Codon 3 insC 27 76 135 110
2 KK 15 Codon 39 delGGAA 35 76 162 55
3 HK 12 Codon 224 delAGCT 28 61 134 44
4 SS 12 IVS2+1G->C 30 68 182 90
Population
mean (n = 1254)		 12.2 ± 1.8   54.4 ± 11.2 131.6 ± 18.3 169.7 ± 26.2 77.2 ± 39.1  

Thus, the frequency of hypoalphalipoproteinemia due to the apo A-I gene mutations with deleterious potential was estimated at 0.3% (95% CI: 0.1-0.8%) in the population and 6% (95% CI: 2.4-14.4%) in the subjects with low HDL-C levels (below the fifth percentile) in the present study.

Besides the rare mutations described above, we detected three common polymorphisms, a G->A substitution in the promoter region (-76 bp) (34,35), a G->A substitution (GCC->ACC, Ala->Thr) in codon 37 of exon 3 (4), and a C->T substitution in intron 3 (IVS 3 +33) (36). No significant association between these polymorphisms and variability in serum HDL-C or apo A-I levels was observed in 67 children with low HDL-C levels and 150 normolipidemic pupils randomly selected from the 1254 subjects (data not shown).

Table 3. Sequence and position of the primers used in PCR and DNA sequencing
Region Primer Sequence Positiona Length of amplicon (bp)
Promoter 1 5[prime]-GACCCCACCCGGGAGACCTGCAAGC-3[prime] 208-232 265
2 5[prime]-CTCTAAGCAGCCAGCTCTTGCAGGGCCT-3[prime] 445-472
Exon 1 3 5[prime]-GACCCTGGCTGCAGACATAAATAGG-3[prime] 423-447 115
4 5[prime]-CTGAACCTTGAGCTGGGGAGCCA-3[prime] 515-537
Exon 2 5 5[prime]-AAGGCACCCCACTCAGCCAGGCCCT-3[prime] 645-669 133
6 5[prime]-GATGGTTGGCTCCTAGGTTAGGGGA-3[prime] 753-777
Exon 3a 7 5[prime]-CTCAGATCTCAGCCCACAGCTGG-3[prime] 879-901 179
8 5[prime]-ACTGGGACACATAGTCTCTGCCGCT-3[prime] 1033-1057
Exon 3b 9 5[prime]-CCACTGTGTACGTGGATGTGCTCAA-3[prime] 1004-1028 186
10 5[prime]-CTCATCAGATATTAGGTGAGGACT-3[prime] 1166-1189
Exon 4a 11 5[prime]-GTGTCACCCAGGGCTCACCCCTGA-3[prime] 1601-1624 270
12 5[prime]-ACTTCTTCTGGAAGTCGTCCAGGTA-3[prime] 1846-1870
Exon 4b 13 5[prime]-ATCTGGAGGAGGTGAAGGCCAAGG-3[prime] 1814-1837 223
14 5[prime]-AGATGCGTGCGCAGCGCGTCCACAT-3[prime] 2012-2036
Exon 4c 15 5[prime]-TGAGCCCACTGGGCGAGGAGATG-3[prime] 1969-1992 205
16 5[prime]-GCTTGGCCTTCTCGCTGAGC-3[prime] 2154-2173
Exon 4d 17 5[prime]-ACGCCAAGGCCACCGAGCATCTGAG-3[prime] 2126-2150 230
18 5[prime]-CCAAAAGAAAGAAGCTGCTT-3[prime] 2336-2355
aNucleotide numbering follows the procedure of Sholders et al. (44).

DISCUSSION

In the present study, based on a survey of 1254 schoolchildren, we screened the apo A-I gene for mutations associated with low HDL-C and found four kinds of mutations with deleterious potential in four individuals. Two of the frameshift mutations (codon 3 insC and codon 39 delGGAA) are predicted to contain only 33 and 40 amino acids, respectively, of the N-terminal end of apo A-I (Fig. 4). Such extremely short and anomalous apo A-I molecules are considered completely defective. The third frameshift mutation (codon 224 delAGCT), which is in the C-terminal side of apo A-I, was predicted to be 228 amino acids instead of the 243 amino acids in the mature sequence. The C-terminal region (residues 220-243) has been shown to play an important role in lipid binding in the interaction of HDL with cell membranes and in the modulation of in vivo catabolism (12,37-39). Therefore, it is likely that the mutant apo A-I that is truncated in the C-terminal region is subject to rapid catabolism. The splice site mutation at the conserved GT dinucleotide of the 5[prime] splice donor site in intron 2 is also predicted to be non-functional because splicing no longer occurs at this site. The subject with a 4 bp deletion at codons 39 and 40 has another missense mutation at codon 38 adjacent to the deletion site, and both mutations were transmitted from his mother with hypoalpha-lipoproteinemia (data not shown). The substitution of Phe for Leu in codon 38 is unlikely to be important in these subjects, because the apo A-I is completely defective due to the other frameshift mutation. In addition, the missense mutations at codon 35 (Gly->Ser) and codon 38 (Leu->Phe) are not likely to cause low HDL-C levels, because the region containing codons 35 and 38 is not key to the biological function of apo A-I (11). It seems that the two missense mutations are rare variants and were detected by chance in the children with low HDL-C levels.

The apo A-I and HDL-C levels of the four children with apo A-I gene mutations with deleterious potential were reduced to approximately half the normal levels. In general, homozygotes for the deleterious apo A-I mutation are deficient in plasma HDL and apo A-I, and heterozygotes have half the normal plasma apo A-I and HDL levels (4,6,11,21-28,30,31,33). Therefore, hypo-alphalipoproteinemia due to the apo A-I gene mutations described here is possibly transmitted as an autosomal dominant trait.

As to population-based studies, two given mutations of the apoA-I gene, one null mutation called apo A-I(5fs)Pisa and one missense mutation called apo A-I(L141R)Pisa, were screened in 477 inhabitants in Tuscany, Italy. One subject had apo A-I(L141R)Pisa (26). In Germany, a large scale screen of apo A-I variants was performed on blood samples from 32 000 newborns using an isoelectrophoretic focusing method, and 17 apo A-I variants (0.05%) with charge differences were detected (40). This method, however, cannot detect apo A-I variants with electrophoretically neutral amino acid substitutions or the apo A-I gene mutations that result in either absent or extremely low concentrations of apo A-I in plasma. DNA sequence analysis can detect such mutations. Indeed the latter type of apo A-I gene mutation was detected at relatively high frequencies in the present study.

Although all the subjects analyzed in this study live in a small rural town, mutations in the apo A-I gene varied with the subjects having hypoalphalipoproteinemia, and no founder effect was observed. These data suggest that the apo A-I gene mutations causing familial hypoalphalipoproteinemia were heterogeneous. In this study, we did not use Southern blot analysis, which can detect large gene rearrangements. Furthermore, the mutation detection rate for SSCP analysis might be at most 90% (41). There is a possibility that some mutant apo A-I genes were missed in the present study. Despite technical limitations and lack of founder effect, our data suggest that autosomal dominant hypoalphalipoproteinemia due to apo A-I gene mutations is relatively common. Based on our data, the frequency of individuals with familial hypoalphalipoproteinemia due to mutations of the apo A-I gene is estimated at 6% (95% CI: 2.4-14.4%) in the subjects with low HDL-C levels and 0.3% (95% CI: 0.1-0.8%) in the general population of children. The frequencies of mutant apo A-I genes in the present study, however, may not apply in other populations. Further studies of screening apo A-I gene mutations in other populations are needed to estimate the frequency of mutant apo A-I genes with deleterious potential in the general population.

Low serum HDL-C and apo A-I levels are strongly associated with an increased risk for CHD (1-7). Genest et al. (20) reported that ~40% of patients with premature CHD have hypoalphalipoproteinemia, and that decreases in HDL-C and apo A-I levels were among the most common plasma lipid abnormalities in CHD cases. Our data suggest that plasma apo A-I and HDL-C levels in heterozygotes for the deleterious apo A-I gene mutations are below the first and second percentiles of the general population distribution, respectively. Therefore, hypoalphalipoproteinemia due to apoA-I gene mutations is likely to be strongly associated with premature CHD. Further studies to reveal the frequencies of the deleterious apo A-I gene mutations in premature CHD patients are now underway.

MATERIALS AND METHODS

Subjects

This study is based on a school survey in a rural town located ~50 km northeast of Tokyo. A total of 1254 schoolchildren (692 boys and 562 girls) who were 9-15 years old with a mean age (±SD) of 12.2 ± 1.8 years, participated in this study. Informed consent was obtained from parents with the agreement that the results of DNA analyses were not revealed to them.

Biochemical analysis

Venous blood was collected after overnight fasting. Serum total cholesterol, HDL-cholesterol and triglyceride levels were measured by standard enzymatic methods described elsewhere (4). Serum levels of apo A-I were measured using turbidity immunoassays (42). Lipid and apolipoprotein values are presented as mg/dl.

DNA analysis

Genomic DNA was isolated from peripheral leukocytes according to the method of Kunkel et al. (43). Each exon, exon-intron boundary and the promoter region of the apo A-I gene was amplified from the genomic DNA using nine PCR primer pairs (Table 3) that were designed to amplify 115-270 bp fragments. SSCP analysis was carried out on 8% non-denaturing polyacrylamide gels at 10°C, using an electrophoretic apparatus equipped with a water jacket (Atto, Tokyo, Japan). Tris-MES-EDTA (pH 6.8) buffer was used according to the method of Kukita et al. (45). The SSCP patterns were visualized using silver staining. Direct sequencing of PCR amplification products was performed using the Sequenase PCR Product Sequencing kit (Amersham-Pharmacia-Biotech, UK). Screening of the two missense mutations was performed by restriction fragment analysis. For the missense mutation at codon 35 (Gly->Ser), a 186 bp fragment was amplified with primers 9 and 10 (Table 3) and was digested with AluI. For the missense mutation at codon 38 (Leu->Phe), a 96 bp fragment was amplified with primer 9 (Table 3) and the mismatched reverse primer (5[prime]-TGGGTCCTTACTTAGCTGTTTTTC-3[prime]) and was digested with TaqI.

Statistical analysis

The correlation coefficients for serum HDL-C and apo A-I levels were calculated by Spearman’s rank correlation coefficient test.

ACKNOWLEDGEMENTS

This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, and a grant from the Uehara Memorial Foundation.

ABBREVIATIONS

apo A-I, apolipoprotein A-I; CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LCAT, lecithin:cholesterol acyltransferase; SSCP, single strand conformation polymorphism.

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*To whom correspondence should be addressed. Tel: +81 298 53 3352; Fax: +81 298 53 3333; Email: kkimiko@md.tsukuba.ac.jp

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