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Clinical Chemistry 43: 13-17, 1997;
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(Clinical Chemistry. 1997;43:13-17.)
© 1997 American Association for Clinical Chemistry, Inc.

Articles

Association between genetic variations of apo AI-CIII-AIV cluster gene and hypertriglyceridemic subjects

Seung Ho Hong1, Woo Hyun Park2, Chung Choo Lee2, Jung Han Song3 and Jin Q Kim4,a

1 Departments of Molecular Biology and
2 Biology, SRC for Cell Differentiation, Seoul National University, Seoul, Korea.

3 Department of Clinical Pathology, Dankook University Hospital, Cheonan, Korea.

4 Department of Clinical Pathology, Seoul National University Hospital, Seoul, Korea.
a Address correspondence to this author at: Division of Clinical Chemistry, Department of Clinical Pathology, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110–744, Korea. Fax 82-2-745-6653.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Several studies have suggested that genetic variations of the apolipoprotein (apo) AI-CIII-AIV cluster gene are associated with hyperlipidemia or atherosclerosis. These investigations were carried out mainly with Caucasian groups; there have been few associated studies involving non-Caucasian groups. This study was conducted to elucidate the association between five restriction fragment length polymorphisms (RFLPs) of the apo AI-CIII-AIV cluster gene and Korean hypertriglyceridemic subjects. The rare allele frequencies of the XmnI and SstI polymorphic sites in the patients were significantly higher than those of the control group (P <0.05). These two polymorphic sites had relation to linkage disequilibrium in the hypertriglyceridemic subjects ({Delta} = -0.2733). In addition, S2 allele frequency of the SstI RFLP in Koreans was more frequent than that of Caucasians reported previously. The rare allele of XmnI and SstI polymorphic sites was associated with increased triglyceride concentrations in the hypertriglyceridemic group (P <0.005). Koreans have a much lower prevalence of hyperlipidemia than Caucasians. Nevertheless, this study showed a similar trend with results from Caucasian groups, thereby confirming that genetic variations of the apo AI-CIII-AIV cluster gene are likely to be significant markers for hypertriglyceridemic sub-jects. Thus, RFLP loci of the apo AI-CIII-AIV cluster gene may be a useful genetic marker for clinical or population studies.


Key Words: indexing terms: hypertriglyceridemia • restriction fragment length polymorphism • allele frequency • atherosclerosis


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Rather than single gene defect, impaired functions in two or more of the many genes that control lipid transport and metabolism have been suspected to cause inherited lipoprotein disorders or atherosclerosis. The apolipoprotein (apo) AI-CIII-AIV cluster gene is one of such groups.1 The products of apo AI, CIII, and AIV genes, together with apo AII, are the major protein components of high-density lipoproteins (HDLs). Each of them has been shown to modify the activity of lecithin:cholesterol acyltransferase in vitro (1)(2). The gene coding for apo AI-CIII-AIV occurs in a tight cluster spanning ~15 kilobases on the long arm of human chromosome 11 (3), where the apo CIII gene is transcribed in the opposite direction to the apo AI and AIV genes.

More than 10 common polymorphisms within the apo AI-CIII-AIV cluster gene have been detected (4)(5), and several studies have suggested associations between some restriction fragment length polymorphism (RFLP) loci of this cluster gene and variations in plasma lipid concentrations (6)(7), although the results have not always been concordant in general populations. The apo AI-CIII-AIV cluster gene has been suggested to be very probably the cause of hyperlipidemia and atherosclerosis. For example, the rare allele of the SstI polymorphism in the 3' noncoding region of the apo CIII gene has mainly been associated with hypertriglyceridemia (8)(9)(10)(11)(12)(13). A few studies have also shown an increased frequency of the allele in patients with coronary artery disease (CAD) (14)(15)(16). The rare allele of the XmnI polymorphism 5' of the apo AI gene appears to be a marker for familial combined hyperlipidemia (FCHL) (17)(18) or hypertriglyceridemia (19). The PstI polymorphism has been reported to show an association with decreased HDL-cholesterol concentrations (20)(21) and with angiographically detected premature CAD (22). It has also been reported to show an association with apo AI concentrations in healthy subjects (20). The two studies have indicated that the G to A mutation at bp position 75 in the apo AI promoter is associated with increased concentrations of HDL-cholesterol (23)(24). These results therefore indicate that genetic variations in this cluster gene influence plasma lipid metabolism.

Association studies of the apo AI-CIII-AIV cluster gene have mainly reported on Caucasian populations. There have, however, been few investigations of non-Caucasian groups. There have been no association reports on Oriental groups, except for a Japanese population (25)(26). In view of the importance of the apo AI-CIII-AIV cluster gene as a major marker for hyperlipidemia, the present study investigated possible associations between variations of the five RFLP sites (XmnI, G->A, PstI, SstI, and HincII) in this cluster gene and plasma lipid concentrations in Korean hypertriglyceridemic subjects.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study subjects
Seventy-seven subjects (73 males, 4 females) with primary hypertriglyceridemia were recruited from the Lipid Clinic at Seoul National University Hospital, Seoul, Korea. Subjects with a triglyceride concentration >2.71 mmol/L were included in the hypertriglyceridemic group. Patients with secondary hyperlipidemia, hypertension, diabetes, and endocrine or metabolic disorders were excluded from this group. The control group consisted of 92 individuals (70 males, 22 females) within the same age range as the patients, who were randomly selected via health screening at the same hospital. The normotriglyceridemic control group was defined as having cholesterol concentrations <75th centile for age and gender and triglycerides <2.15 mmol/L. All subjects gave their informed consent before participation. Clinical details for these groups are summarized in Table 1 .


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  		Table 1. Mean age (year ± SD) and lipid profiles (mmol/L ± SD) of the study subjects.

determination of lipid parameters
Blood samples were obtained in EDTA tubes from individuals who had been fasting for 12–16 h. Concentrations of plasma cholesterol and triglyceride were measured by enzymatic colorimetry methods with commercial kits (Boehringer Mannheim, Mannheim, Germany) and a Hitachi 747 automated chemistry analyzer. The day-to-day CVs were 2.5% for cholesterol and 5.1% for triglycerides. HDL-cholesterol was determined by measuring cholesterol in the supernatant liquid after precipitation of the plasma with MgCl2 and dextran sulfate, with a Gilford Impact 400E automated analyzer with reagents and calibrators from Boehringer Mannheim. The day-to-day CV of HDL-cholesterol was 4.0%.

dna analysis
Total genomic DNA was prepared from the leukocytes of 10 mL of blood after lysis of red blood cells (27). For G to A mutation (HpaII) and SstI and HincII polymorphisms, DNA was amplified by PCR. The G to A mutation is at bp position 75 in the promoter region of the apo AI gene. Primer sequences and procedures for PCR amplification have previously been described (28). Fragments of 175 bp and 75 bp identify the G allele (presence of cutting site), while a fragment of 258 bp identifies the A allele (absence of cutting site). For the SstI polymorphism of 3' untranslated region of the apo CIII gene, primer sequences and procedures for PCR amplification have been described (29). Fragments of 596 bp for the S1 allele (absence of cutting site) and of 371 and 225 bp for the S2 allele (presence of cutting site) were produced. For the HincII restriction site at exon 3 of the apo AIV gene, procedures for PCR amplification and digestion were as described (30). Here, fragments of 615, 262, and 135 bp for the N allele and of 877 and 135 bp for the S allele were produced. For XmnI and PstI polymorphisms, Southern transfer onto nylon membrane (Hybond-N, Amersham, UK) and hybridization with digoxigenin-labeled clone pAI-113 of apo AI cDNA were carried out as described elsewhere (31), according to the specifications of the manufacturer (Boehringer Mannheim). The probe was kindly supported by J.L. Breslow (The Rockefeller University, New York, NY). The PstI polymorphic site maps to the intergenic sequence between the apo AI and CIII genes. It shows a two-allele polymorphism with bands at 2.2 kb (P1 allele) or 3.2 kb (P2 allele). The XmnI polymorphism is located in the 5' flanking region ~3.7 kb from the cap site of the apo AI gene. It gives a band of 8.3 kb (X1 allele, absence of site) or 6.6 kb (X2 allele, presence of site).

data analysis
The counting method was used for the estimation of the apo AI-CIII-AIV cluster gene frequencies. Differences of genotype distributions in the two groups were calculated by using 2 x 2 contingency tables. The {chi}2 test was used to apply for Hardy–Weinberg equilibrium, while the one-way analysis of variance (ANOVA) test was performed to compare the mean levels of lipid parameters among different genotypes. Statistical significance was accepted at the P = 0.05 level. The degree of nonrandom association was determined by calculation of the delta value ({Delta}) between the two polymorphic sites at the apo AI-CIII-AIV cluster gene (32).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
As shown in Table 1Up , the normo- and hypertriglyceridemic groups did not differ significantly with respect to age. The hypertriglyceridemic group had significantly higher plasma total cholesterol and triglyceride (P <0.005) or lower HDL-cholesterol concentrations (P <0.05) than the normotriglyceridemic group. Allele frequencies of five RFLPs in the hypertriglyceridemic and control subjects are given in Table 2 . The heterozygosity and polymorphism information content (PIC) values are also shown. The rare allele frequencies of the XmnI and SstI sites of the hypertriglyceridemic subjects showed a significantly higher increase than those of the control group (P <0.05). None of the other polymorphisms showed a difference in allele frequency between the two groups. The PIC of the XmnI, SstI, and HincII RFLP showed relatively high values in the two groups. At all sites except one, genotype distributions did not differ from those expected for Hardy–Weinberg proportions. The SstI RFLP deviated from this equilibrium due to the relatively rare S2 homozygote in the control group ({chi}2 = 9.59, df = 1, P <0.005). The degree of linkage disequilibrium between polymorphisms was estimated by using the standardized disequilibrium statistic, {Delta}. Some RFLP sites at this loci are in apparent linkage disequilibrium (data not shown).


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  		Table 2. Comparison of allele frequencies in control and hypertriglyceridemic groups.

Table 3 presents the comparison of lipid parameters in the SstI and XmnI polymorphisms. Triglyceride concentrations varied significantly among genotypes of XmnI and SstI sites in the hypertriglyceridemic subjects (ANOVA test, P <0.05). In particular, the X2X2 and S2S2 homozygote of the patients is associated with the highest triglyceride concentrations. Cholesterol concentrations differed significantly among genotypes of SstI site in the hypertriglyceridemic subjects (ANOVA test, P <0.05).


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  		Table 3. Comparison of lipid concentrations (mean ± SD, mmol/L) according to apo CIII/SstI and AI/XmnI genotypes.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Hypertriglyceridemia is a common metabolic disorder that may be the result of defective degradation of triglyceride-rich lipoproteins, impaired clearance from plasma, or a combination of both. A number of epidemiological studies have shown that in addition to environmental factors, genetic mechanisms may play a role in determining susceptibility to hypertriglyceridemia.

In the present study we determined allele frequencies of the apo AI-CIII-AIV cluster gene in normo- and hypertriglyceridemic groups. We showed that the rare allele frequency of the SstI RFLP is higher in the hypertriglyceridemic group than in control subjects (P <0.05). The rare allele frequency of the controls was similar to that of Japanese and Chinese populations, and more frequent than in Caucasians. In most but not all studies, which have been mainly with Caucasians, the rare allele of the SstI polymorphism has been demonstrated to be associated with hypertriglyceridemia. The triglyceride concentrations of our data were significantly different among the SstI genotypes in the hypertriglyceridemic group (P <0.005); in particular, they showed the most increased values in the S2 homozygote. Thus, the S2 allele might be a cause of increased triglyceride concentrations. Cholesterol concentrations also varied significantly among the SstI genotypes in the hypertriglyceridemic group without gene dosage effect (P <0.005). Apo CIII inhibits lipoprotein lipase hydrolysis of triglycerides as well as the uptake of VLDL and chylomicron remnants by the liver. Thus, it might affect triglyceride as well as cholesterol concentrations. Furthermore, Ito et al. (33) reported that overexpression of human apo CIII causes severe hypertriglyceridemia in transgenic mice. However, the SstI polymorphic site is located in the 3' noncoding region of the apo CIII gene. As the sequence change of the SstI site does not alter an amino acid, the rare allele of the SstI RFLP is likely involved in determining differences of triglyceride concentrations by linkage disequilibrium with other functional sequences in or nearby the apo CIII gene. Other studies suggested that certain haplotypes generated from the SstI RFLP and promoter variants of the apo CIII gene may protect or predispose to hypertriglyceridemia (34)(35). In addition, the SstI polymorphism may also likely have some influence on mRNA stability (36).

The rare allele of the XmnI polymorphism of the apo AI gene is also associated with hypertriglyceridemia in Koreans. Triglyceride concentrations varied significantly among the genotypes in the hypertriglyceridemic group (P <0.005). It is important to examine the possibility that the associations found in the XmnI and SstI polymorphisms may be related each other. In the present study, the XmnI and SstI polymorphisms were in apparent linkage disequilibrium ({Delta} = -0.2733). A mechanism that could explain this possibility, and one that cannot be excluded, is that the XmnI variable site, which occurs within the 5' flanking region ~3.7 kb from the cap site of the apo AI gene, may have a direct effect on the rate of the apo AI gene transcription. Thus, the X2 homozygote might be a cause of increased triglyceride concentrations, or unknown mutations in apo AI-CIII-AIV might exist in linkage disequilibrium with XmnI polymorphism. Thus, the mutations may cause overexpression of apo AI. There have been fewer reports of hypertriglyceridemia being linked with XmnI RFLP (19) than there have of its being linked with SstI. Some studies have suggested that XmnI polymorphism is mainly associated with FCHL (17)(18). According to the family history of FCHL, hypertriglyceridemia is also a feature. Although the hypertriglyceridemic subjects of this study were not >95th centile in cholesterol concentrations for age and gender, these concentrations were significantly higher in the patients than in the controls (P <0.005). Since individuals with FCHL might be included within the group of hypertriglyceridemic subjects, the frequency of the XmnI rare allele may increase slightly in this study.

In the present study, allele frequencies of G->A, PstI, and HincII polymorphisms did not differ between the two groups. Also, some studies have suggested that these polymorphic sites do not serve as a useful DNA marker for dyslipidemia or atherosclerosis. Although the association of the G to A mutation with plasma HDL-cholesterol concentrations was reported, it has been recently disputed (37).

Association studies of the cluster gene loci with plasma lipid concentrations have been performed mainly with Caucasians, but results have been inconsistent. There have been only a few studies involving Orientals, including Japanese and Chinese populations. There is a much lower prevalence of hyperlipidemia in Asian groups than in Caucasians. Hyperlipidemia is influenced by genetic constitution as well as by environmental factors, including lifestyle, diet, and smoking. In spite of differences in the genetic background, polymorphism data for various ethnic groups may be consistent. In conclusion, our data confirmed the results of previous investigations that the apo AI-CIII-AIV gene cluster is involved in hypertriglyceridemia.


   Acknowledgments
 
We are grateful to J.L. Breslow (The Rockefeller University, New York, NY) for supporting the pAI-113 probe. This work was supported in part by grants from the Seoul National University Hospital (04-96-034) and the Korean Sciences and Engineering Foundation through the Research Center for Cell Differentiation (95-2-1).


   Footnotes
 
1 Nonstandard abbreviations: apo, apolipoprotein; RFLP, restriction fragment length polymorphism; CAD, coronary artery disease; FCHL, familial combined hyperlipidemia; and PIC, polymorphism information content.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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