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Annals of Clinical & Laboratory Science 34:443-448 (2004)
© 2004 Association of Clinical Scientists

Association of Apolipoprotein E Genotypes with Serum Lipid Profiles in a Healthy Population of Taiwan

Shu-Kai Lin1, Jau-Tsuen Kao2, Shih-Meng Tsai3, Li-Yu Tsai1,4, Mei-Nung Lin1, Chung-Jen Lai4 and Way-Li Zhong4
1 Department of Clinical Biochemistry, Kaohsiung Medical University, Kaohsiung; 2 School of Medical Technology, National Taiwan University, Taipei; 3 School of Technology for Medical Sciences and 4 Department of Public Health, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Address correspondence to Li-Yu Tsai, Ph.D., Department of Clinical Chemistry, School of Technology for Medical Sciences, Kaohsiung Medical University, No. 100 Shi-Chuan 1st Road, San Ming District, Kaohsiung, Taiwan; tel 886 7 312 1101 ext 7262; fax 886 7 237 0544; e-mail tsliyu{at}kmu.edu.tw.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Apolipoprotein E (apoE, protein; APOE, gene) plays a major role in lipoprotein metabolism and lipid transport. Many investigators have described associations between apoE genotypes, coronary artery disease (CAD), and other risk factors. The aim of this study was to investigate the association between apoE genotypes and serum lipid profiles in a healthy population of 220 volunteers at Kaohsiung in Taiwan. Other CAD risk factors such as serum levels of apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), homocysteine (Hcy), folate, and vitamin B12 were also measured. ApoE genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In the study population, the frequency of apoE allele {varepsilon}3 was greatest (85.2%); the frequency of {varepsilon}2 was 8.4%; and that of {varepsilon}4 was 6.4%. The serum apoA-1/apoB ratio showed significant difference among the 3 apoE genotype groups (p .0001); the apoA-1/apoB ratio was 1.9 ± 0.1 (mean ± SD) in the {varepsilon}2 group, vs 1.4 ± 0.04 and 1.5 ± 0.12 in the {varepsilon}3 and {varepsilon}4 groups, respectively. No significant associations were found between APOE alleles and the serum levels of the various lipids or other CHD risk factors.

(received 10 June 2004; accepted 23 August 2004)

Keywords: apolipoproteins E, A-I, B, polymerase chain reaction-restriction fragment length polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Apolipoprotein E (apoE) is a 34.2 kDa protein that is incorporated into serum lipoproteins and directs their catabolism via binding to receptors. ApoE modulates the catabolism of triglyceride-depleted remnants of chylomicrons (CM) and very low-density lipoprotein (VLDL). The APOE gene, together with the ApoC-I, ApoC-I’, and ApoC-II genes, forms a gene cluster on the long arm of chromosome 19 (19q13.2) [1]. APOE is polymorphic with three common alleles ({varepsilon}2, {varepsilon}3, and {varepsilon}4) coding for 3 isoforms (E2, E3, and E4), which produce 3 homozygous (E2/E2, E3/E3, and E4/E4) and 3 heterozygous (E2/E3, E2/E4 and E3/E4) phenotypes in the human population [2]. The frequencies of the {varepsilon}2 (112cys and 158cys), {varepsilon}3 (112 -cys and 158arg), and {varepsilon}4 (112arg and 158arg) alleles are relatively constant in adult Caucasians (8%, 78%, and 14%, respectively) [3]. However, the frequencies of these alleles in other populations are not identical.

Individuals carrying the {varepsilon}2 allele display high levels of apoE and low levels of plasma total cholesterol (TC), low density lipoprotein (LDL)-cholesterol, apoB, and lipoprotein(a) [Lp(a)], whereas carriers with the {varepsilon}4 allele show the opposite [4]. The influence of apoE on serum lipid levels is often suggested to have major implications for the risk of coronary artery disease (CAD); individuals with the {varepsilon}4 allele are at higher risk compared to those with the {varepsilon}2 allele [4]. The frequency of APOE {varepsilon}4 alleles is high in Alzheimer’s disease and other neurodegenerative disorders [5]. The homozygous {varepsilon}2 genotype is a prerequisite for type III hyperlipoproteinemia [6].

Lipoprotein(a) [Lp(a)] is a modified form of LDL to which a large glycoprotein, apolipoprotein(a) [apo(a)], is covalently bound by a disulfide linkage [7,8]. The clinical correlates of impaired thrombolysis in patients with excess of Lp(a) include (i) increased tissue plasminogen activator inhibitor levels, (ii) decreased activity of the tissue plasminogen activator in young survivors of myocardial infraction (MI), and (iii) increased Lp(a) levels in survivors of MI without recanalization of their infarct-related arteries [9,10].

Epidemiologic studies indicate that serum apolipoprotein concentrations and the risk of coronary heart disease (CHD) are related [11–15]. High serum concentrations of apoB, a protein component of LDL, are associated with increased risk of CHD, and high serum concentrations of apoA-I, a major protein component of HDL, are inversely associated with CHD risk. In addition, the apoB to apoA-I ratio (ApoB/ApoA-I) can be used as a marker for CHD [16]. Shen et al [17] showed that serum levels of triglyceeride (TG) and apoA-I did not differ according to apoE genotypes, while the serum level of apoB was significantly different according to apoE genotypes (p <0.05), both in healthy and CHD subjects.

No data are available for the relationship between apoE polymorphism and serum lipid levels or other CHD risks factors in inhabitants of Kaohsiung in Southern Taiwan. In this study, we investigated the association of apoE polymorphism with lipids and apolipoprotein levels in a healthy population living in Kaohsiung.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Blood biochemistry.  All volunteers gave their informed consent to take part in this study. Blood samples were collected in EDTA-containing tubes from 220 healthy individuals after 12 hr of fasting. Plasma was separated within 30 min and stored on ice. Hcy, vitamin B12, and folate were analyzed by the Immulite 2000 analyzer. Lp(a), apoA-I, and apoB were analyzed by the Beckman Array analyzer using nephelometric methods that measure precipitate formation in the antigen-antibody reactions. Serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured by the Beckman CX5 analyzer. Enzymatic methods with an endpoint reaction type were used for the TC and TG measurements. Direct methods were used for the HDL-C and LDL-C measurements. The very low-density lipoprotein cholesterol (VLDL-C) level was calculated by the equation: VLDL-C = TC-HDL - LDL.

Amplification of apoE sequences from genomic DNA for restriction isotyping.  After leukocyte DNA was extracted, the 244 bp sequence of APOE was amplified by PCR in a DNA Thermal Cycler (Perkin Elmer Cetus 2400) using oligonucletide primers F4 (5'-ACAGAATTCGCCCCGGCCTGGTACAC-3') and F6 (5'-TAAGCTTGGCACGGCTGTCCAAGGA -3'). Each amplification reaction contained 600 ng of leukocyte DNA, 1 pmol/µl of each primer, 10% dimethyl sulfoxide, and 1 unit/µl of Taq DNA polymerase in a final volume of 50 µl. Each reaction mixture was heated at 94°C for 4 min for denaturation, and subjected to 35 cycles of annealing (62°C for 15 sec) and extension (72°C for 2 min).

Restriction isotyping of amplified apoE sequences with HhaI and gel analysis.  After PCR amplification, 5 units of HhaI (New England Biolabs) were added to each PCR product and digested at 37°C for 3 hr. The digested product was loaded onto a 12% nondenaturing polyacrylamide gel and electrophoresed for 2 hr at constant voltage (60 V). The gel was stained with ethidium bromide (0.2 mg/L) for 10 min and visualized under UV illumination.

Statistics.  Data were analyzed by SAS for Windows (Version 6.12). A p value <0.05 was considered as a significantly statistical difference. One-way analysis of variance (ANOVA) was performed to test the null hypothesis of equality of lipid levels and other cardiovascular risk factors among the apoE genotype groups.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The frequencies of the {varepsilon}2, {varepsilon}3, and {varepsilon}4 alleles were estimated by the gene counting method (Table 1Go). Only 5 of the apoE genotypes were included in the estimation of the impact of apoE polymorphism on quantitative traits. Subjects with the E2/E4 genotype were not included, because of the potentially opposite effects of the {varepsilon}2 and {varepsilon}4 alleles on serum lipid levels. Subjects were pooled into 3 groups ({varepsilon}2-, {varepsilon}3-, and {varepsilon}4-containing genotypes) to explore the allelic effect and to increase statistical power. The classification of APOE genotype was conducted on the entire group of 220 volunteers; however, only 182 volunteers underwent the tests of serum lipid profiles and other CHD risk factors, because of loss of samples during blood collection.


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  		Table 1. Allele frequencies and prevalence of ApoE genotypes in a healthy population of Kaohsiung in Taiwan.
 
The allele frequencies and prevalence of apoE genotypes results are shown in Table 1Go. Most participants (85.2%) carried at least one {varepsilon}3 allele, 8.4% carried an {varepsilon}2 allele, and 6.4% carried an {varepsilon}4 allele. Table 2Go shows the results (mean ±SD) for lipid constituents (total cholesterol, HDL cholesterol, LDL cholesterol, and TGs) and the other CHD risk factors, categorized according to apoE genotype groups. There were no significant differences in the levels of the serum lipids, Lp(a), Hcy, folic acid, or vitamin B12 among the 3 apoE genotype groups. The serum apoA-I/apoB ratio showed significant difference among the 3 apoE genotype groups (p .0001); the apoA-I/apoB ratio averaged 1.9 ± 0.1 (SD) in the {varepsilon}2 group, vs 1.4 ± 0.04 and 1.5 ± 0.12 in the {varepsilon}3 and {varepsilon}4 groups, respectively.


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  		Table 2. Serum concentrations of lipids and various CHD risk factors in relation to ApoE genotype groups.
 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In our study population, the frequency of apo E allele {varepsilon}3 was greatest (85.2%); the frequency of {varepsilon}2 was 8.4%; and that of {varepsilon}4 was 6.4%. Results of studies in other populations are listed in Table 3Go. The frequency of the {varepsilon}3 allele is generally the highest, about 85%. The populations differ substantially in the frequencies of {varepsilon}2 and {varepsilon}4. In Taiwanese subjects, Wu et al [18] found only 4 genotypes, namely E3/E3, E3/E4, E2/E3, and E2/E4. When the frequencies of the alleles in our study are compared with those in the Wu et al study [18], the results are approximately the same. Our results are also similar to those reported by Kao et al [19]. Table 3Go shows that there were no pronounced differences in the distribution of the alleles in the various populations, except the results in Norway [33] and Italy [29], which had higher {varepsilon}4 frequency. However, different typing methods might have been responsible for these discrepancies.


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  		Table 3. Comparisons of apoE allele frequencies in different populations or ethic groups.
 
In some studies, associations of apoE polymorphism with serum lipids were consistent with the well-documented effects of apoE [20–22]; {varepsilon}4 increased both serum total and LDL cholesterol levels, while {varepsilon}2 decreased these levels. Correlation between apoE polymorphism and HDL cholesterol level was noted in some studies [23,24], but not in others [25].

The level of serum TGs seems to decrease from the {varepsilon}2 group to the {varepsilon}4 group in our study. This could reflect the fact that the values were not well-distributed, but there were no statistically significant differences in the concentrations of TGs among the 3 groups. Similarly, the mean level of LDL cholesterol in the {varepsilon}2 group was the lowest among these 3 groups; however, the opposite was observed in the levels of VLDL and HDL, which did not show any significant differences among the groups.

Some risk factors, namely Lp(a), Hcy, apoA-I, and apoB, were also tested in this study. There were no significant relationships between the Hcy, La(a), folate, and vitamin B12 and the apoE genotype. Only the ratio of apoA-I/apoB, which is often used clinically as a marker for CHD, showed significant differences among the 3 apoE genotypes.

The variations at the apoE locus affect the catabolism of apoB-containing lipoproteins, intestinal absorption of dietary cholesterol, and the receptor binding ability of lipoprotein [26]. In the present study, we did not find any effects of apoE genotypes on TC, LDL-C, HDL-C, and TG levels. However, similar negative results have also been found in other populations [27–29].

In our study, in comparison with the {varepsilon}3 and {varepsilon}4 groups, the {varepsilon}2 group had the highest apoA-I/apoB ratio, as shown in Table 2Go. Shen et al [17] found that serum levels of TG and apoA-I did not differ according to apoE genotypes, while the serum level of apoB was significantly related to apoE genotypes (p <0.05), both in healthy and coronary artery disease groups. They found that apoE concentration was positively correlated with the apoA-I and apoB levels in control subjects. On the other hand, Hsueh et al [30] observed no significant effect of apoE genotypes on apoA-I levels, whereas the E2/E3 genotype had the lowest apoB levels. Further research is needed to explain these apparent inconsistencies with the present findings.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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