Published online before print June 19, 2003, doi: 10.1161/01.ATV.0000082525.84814.A9
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© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Association Between a Novel 11–Base Pair Deletion Mutation in the Promoter Region of the Scavenger Receptor Class B Type I Gene and Plasma HDL Cholesterol Levels in Taiwanese Chinese
From the First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
Correspondence and reprint requests to Yu-Lin Ko, MD, PhD, First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital, No. 199, Tung-Hwa North Rd, Taipei, Taiwan. E-mail koyulin{at}adm.cgmh.org.tw
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Abstract |
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Objective— Scavenger receptor class B type I (SR-BI) is a multiligand cell-surface receptor that mediates the selective uptake of lipid from HDL cholesterol (HDL-C) into cells. This study hypothesized an association between functional variants in the promoter region of SR-BI gene and HDL-C levels.
Methods and Results— We identified 2 novel mutations in the SR-BI gene promoter region by using single-strand conformation polymorphism. One mutation was an 11-bp CCCCGCCCCGT deletion mutation from positions -140 to -150 relative to the transcription start site, corresponding to an Sp1 binding site; the other was a C
T substitution at position -142. Twenty-six of 690 unrelated subjects were heterozygous for the -140 to -150 deletion mutation, and the allele frequency in this population was 0.02. This study showed that the deletion variant prevented binding of Sp1 to this region of the SR-BI promoter and effectively reduced transcriptional activities in HepG2 cells. Notably, the -140 to -150 deletion mutation was significantly associated with increased HDL-C levels and explained 
0.5% of the variation in HDL-C levels in this population.
Conclusions— A genetic variant at the SR-BI gene promoter region might explain a significant proportion of individual differences in HDL-C levels among Taiwanese Chinese. Our results require further replication in an independent population.
Key Words: deletion • mutation • scavenger receptor class B type I • HDL cholesterol
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Introduction |
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Epidemiologic investigations have demonstrated an inverse relation between the plasma HDL cholesterol (HDL-C) level and the incidence of coronary heart disease (CHD).1 The main mechanism of CHD protection of HDL-C is believed to be through reverse transport of cholesterol from arterial cells to the liver.2 In addition, HDL-C uptake by cells involves the selective transfer of cholesterol ester to the cell without HDL protein uptake and degradation, a process termed selective lipid uptake.3 Acton et al4 have demonstrated that scavenger receptor class B type I (SR-BI), a multiligand cell-surface receptor isolated from Chinese hamster ovary cells by expression cloning,5 binds closely with HDL and mediates selective cholesterol uptake in transfected cells. This receptor is mainly expressed in tissues that display selective lipid uptake in vivo, namely, the liver, adrenal gland, and testis.4–7 Further in vivo analyses in mice and rats suggested that SR-BI is crucial in HDL metabolism. For example, SR-BI expression is upregulated in the adrenal gland, where HDL-C is used for steroid hormone synthesis, in response to depleted plasma HDL-C levels in apolipoprotein AI–knockout (KO) mice.6 Adenovirus-mediated overexpression of SR-BI in mouse livers causes a significant reduction in plasma HDL-C levels and a corresponding increase in biliary cholesterol.8 Targeted disruption of the SR-BI gene in mice reduced selective uptake of cholesterol ester from HDL into the liver9 and significantly increased plasma HDL-C.9,10 Furthermore, Acton et al11 also found an association between several single-nucleotide polymorphisms (SNPs) in the coding region of the SR-BI gene and plasma HDL-C/LDL-C levels and body mass index (BMI) in a Spanish population. This association suggests that SR-BI might also influence the metabolism of both lipoprotein classes in humans. Whether genetic variants in the promoter region of the human SR-BI gene influence expression of this gene in vivo and thus, regulate plasma HDL-C levels remain uncertain. This work screened for the SR-BI promoter gene mutation in a Taiwanese Chinese population and identified 2 novel mutations in the promoter region of the SR-BI gene. Additionally, this investigation also examined the effects of these novel mutations on lipoprotein metabolism and their prevalence in the subject Chinese population.
See page 1710
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Methods |
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Study Population
A total of 1103 individuals were recruited for analysis of the genetic determinants of HDL-C levels during routine health examinations after informed consent had been obtained. Three hundred eighty-five subjects were excluded because of major systemic or cardiovascular disease or a history of lipid-lowering medication. Seven other subjects were excluded owing to a shortage of their DNA samples. The final study group thus included 711 individuals (389 men and 322 women; mean±SD age, 55.3±9.9 years). The details of the study population have been described previously.12 The investigation was approved by the Ethics Committee of Chang Gung Memorial Hospital.
Plasma Lipid Measurements
A 5-mL blood sample was obtained from all subjects after a 12- to 14-hour overnight fast. Total cholesterol and triglyceride concentrations were measured by automatic enzymatic colorimetry. HDL-C levels were measured enzymatically after phosphotungsten/magnesium precipitation. Finally, LDL-C was calculated from the Friedewald formula.
Amplification of Genomic DNA Fragments in the Promoter Region of the SR-BI Gene and SSCP
Twenty-four individuals were randomly chosen from among the subjects for polymerase chain reaction (PCR)/single-strand conformational polymorphism (SSCP) analysis. Genomic DNA was prepared from white blood cells by phenol and chloroform extraction. A fragment of 545 bp of the 5'-flanking sequence of the SR-BI gene was then divided into 3 overlapping fragments of 200 bp and subjected to PCR by using specific pairs of primers (Table I; please also see www.ahajournals.org) under the following cycle conditions: 94°C for 10 minutes, 35 times (94°C for 2 minutes, annealing temperature for 1 minute, and 72°C for 2 minutes), and 72°C for 10 minutes. SSCP analysis was performed on commercial, nondenaturing polyacrylamide gels (Pharmacia Biotech) run at 5°C and 25°C as described in written protocols (GeneGel Excel, Pharmacia Biotech). After electrophoresis, the DNA was detected with use of a DNA silver staining kit (Plus One, Pharmacia Biotech).
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Identification of Mutations by Cloning and Direct Sequencing of PCR Products
DNA from samples with different SSCP migration patterns was reamplified by PCR with the primers mentioned earlier. PCR products were then purified and inserted into a plasmid vector (pCRII-TOPO). Chemical transformation of Escherichia coli with use of the recombinant plasmid DNA was conducted with a cloning kit (TOPO TA). Subsequently, the plasmids carrying the insert were selected and purified with a commercially available kit (Mini-prep, Invitrogen). Finally, the inserts were subjected to automated sequencing with M13 forward and reverse primers.
Genotyping of the -140 to -150 11-bp Deletion Mutation in the Study Population
After the deletion mutation was characterized by direct sequencing, subjects were typed by SSCP and also confirmed by PCR product (-111 to -340) digestion, with use of the forward primer 5'-GGGGCTTGTATTGGCGGCCA-3', the reverse primer 5'-GGCACGGTGGATCCGGGACG-3', and the BsmFI restriction enzyme. Alleles with the deletion mutation cannot be digested by BsmFI, unlike the nonmutated allele.
Genotyping of the -142 CT Polymorphism in the Study Population
After the -142 CT mutation was characterized through direct sequencing, subjects were classified according to the results of PCR and restriction enzyme digestion. A fragment of 90 bp (-251 to -340) was amplified by PCR with the forward primer 5'-GGGGCTTGTATTGGCGGCCA-3' and the reverse mismatched primer 5'-AGCGGGCCCGGGGCGGGGTCGGGGCGGCGAC-3'. Notably, the reverse primer was modified (underlined) to create an Hpy99I endonuclease cleavage site for detecting the -142C allele. Finally, the amplified PCR product was digested with Hpy99I, and the resulting fragments, separated by 4% agarose gel electrophoreses (NuSieve), were 90 bp for TT homozygotes, 90 and 59 bp for CT heterozygotes, and 59 bp for CC homozygotes.
Construction of SR-BI Reporter Vectors
A genomic DNA fragment (extending from +33 to -375 relative to the transcription start site) of the SR-BI promoter region was amplified by PCR from individuals who were heterozygous for -142C/T and from those who were compound heterozygous for the -140 to -150 deletion (del)/-142T. The upstream and downstream primers were 5'-AGGGGAGATCTGGGAGGAGG-3' and 5'-AGAGGCACGGTAGATCTGGGACGGCA-3'. The primers were then modified (boldface) to create BglII cutting sites (underlined). Finally, the PCR products were digested with BglII and ligated to the pGL3-basic luciferase expression vector (Promega), creating the plasmids pSRBI wild-type luc, pSRBI -142T luc, or pSRBI -140 to -150del luc.
Cell Culture, Transient Transfection, and Luciferase Assay
HepG2 cells were maintained in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal calf serum and antibiotics. The cells were dispensed into 24-well plates and cultured until 70% to 80% confluence was achieved. Transient transfections were conducted with 3 µL Lipofectamine (Invitrogen), 0.7 µg of the promoter/luciferase reporter plasmids, and 0.1 µg herpes simplex virus thymidine kinase promoter/Renilla luciferase reporter plasmids. Cells were harvested after 24 hours, and luciferase activity was assessed with an assay system (Dual Luciferase Reporter, Promega). Measurements were conducted with a luminometer (TD20/20, Turner) in a single tube, with an initial assay from firefly luciferase being followed by the Renilla luciferase assay. Finally, firefly luciferase activities (relative light units) were normalized by Renilla luciferase activities.
Electrophoretic Mobility-Shift Assay
HepG2 nuclear extracts were prepared from confluent 10-cm dishes by the method described by Dignam et al,13 and HeLa cell nuclear extracts were purchased from Promega. Electrophoretic mobility-shift assay (EMSA) was performed with a commercially available kit (DIG Gel Shift, Roche) according to the manufacturer’s instructions. The oligonucleotide sequences used in the reactions were as follows: wild type, 5'-CCGTCCGATCAGCGCCCCGCCCCGTCC-3'; -142T mutant, 5'-CCGTCCGATCAGCGCCCCGCCCTGTCC-3'; -140 to -150del mutant, 5'-CCGTCCGATCAGCGCC-3'; and Sp1 consensus sequence (Promega), 5'-ATTCGATCGGGGCGGGGCGAGC-3'.
Statistical Analysis
The 
2 test was used to examine differences in categorical variables. The clinical characteristics of continuous variables were expressed as mean±SD and were tested with a 2-sample t test or ANOVA. Furthermore, a general linear model was applied to analyze HDL-C levels with respect to predictors of the investigated genotypes and other confounders. Variables were logarithmically transformed before statistical analysis to meet a normality assumption. Finally, all probability values were calculated on the basis of 2-sided tests, with statistical significance being defined where the probability value was <0.05. An expanded Methods section can be found in the online data supplement available at www.ahajournals.org.
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Results |
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Identification of a DNA Sequence Change in the Promoter Region
A fragment of 545 nucleotides of the SR-BI promoter (from +30 to -515 relative to the translation start site) was screened for polymorphism in the 24 randomly chosen individuals by PCR/SSCP and sequencing. A novel 11-bp CCCCGCCCCGT-del mutation was identified from positions -140 to -150 relative to the transcription start site, which happened to be the third Sp1 binding site (underlined) upstream from the transcription start site (Figure 1 and online Figure I; please see www.ahajournals.org). In addition, another novel mutation (C
T) was identified at position -142 (boldface), which was the first base of the same Sp1 binding site (Figure 1 and online Figure I; please see www.ahajournals.org). These mutations were examined further for all study subjects. Genotype data were available on different numbers of subjects owing to PCR failures (17 for the -140 to -150del mutation, 21 for the 142 CT polymorphism). Both genotypes were identifiable in 690 subjects. Table 1 summarizes the clinical and biometric features of these 690 subjects. Among this group, 26 subjects carried the deletion allele heterozygously, representing an allele frequency of 0.02. Four of these 26 subjects were also -142T allele compound heterozygous carriers. The genotype frequencies for delT and delC were 0.6% and 3.2%, respectively (del indicates the -140 to -150del allele). Moreover, the genotype frequencies for the SR-BI -142CT polymorphism were 2.0%, 23.5%, and 70.7% for TT, CT, and CC, respectively. Finally, the frequency of the SR-BI -142C allele was 0.84, whereas that of the SR-BI -142T allele was 0.14.
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Luciferase Reporter Assays
To determine whether functional differences existed among the different alleles of the SR-BI promoter region, 3 luciferase reporter gene constructs were created containing the wild-type, the -140 to -150del allele, and the -142T allele. As displayed in Figure 2, the relative luciferase activity of the constructs containing the 11-bp deletion was significantly lower than that of the wild-type and -142T constructs (P<0.001 and P<0.001, respectively). Notably, luciferase activity did not differ significantly between the -142T and wild-type constructs (P=0.161).
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Electrophoretic Mobility-Shift Assay
Because the -140 to -150del and -142T mutations lie within the DNA motif for Sp1 recognition, this study examined whether these mutations indeed influenced Sp1 binding. A HepG2 cell nuclear extract was incubated with matching sets of DIG-labeled oligomers corresponding to the wild-type and the 2 mutant sequences from -164 to -138 of the SR-BI promoter, and the DNA-protein complexes were then subjected to EMSA. The nuclear extract produced a major retarded complex when incubated with the wild-type and the mutated -142T sequence (Figure 3A, lanes 2 and 8, respectively). In contrast, the mutated -140 to -150del sequence was incapable of complex formation with the same nuclear extracts (Figure 3A, lane 5). The specificity of DNA-protein interaction was confirmed by competition experiments, in which complex formation was prevented by an excess of unlabeled wild-type oligomer (Figure 3A, lanes 3 and 9) and Sp1 consensus oligomer (Figure 3B, lane3), but not the -140 to -150del mutant oligomer (Figure 3B, lane 5). Figure 3B further confirms that the -140 to -150del mutation disrupted Sp1 binding to the SR-BI sequence. A labeled, consensus Sp1 oligonucleotide bound a protein from HeLa nuclear extracts in the absence but not the presence of unlabeled wild-type and -142T oligomers, which competed effectively for binding to this protein (lanes 7 and 9, respectively), whereas at the same concentration, the mutated -140 to -150del oligomer did not (lane 8).
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Effects of SR-BI Gene Promoter -140 to -150del Mutation on Plasma Lipid Levels
Table 2 lists the effects of the deletion mutation of the SR-BI gene promoter on plasma lipid levels. The SR-BI -140 to -150del mutation was significantly associated with plasma HDL-C levels. Subjects carrying the deletion allele exhibited higher HDL-C levels than did those without this deletion allele (58±19 vs 52±14 mg/dL; P=0.035). No association was noted between the deletion mutation and other lipid variables and BMI. Multiple linear regression analysis of HDL-C levels revealed that besides sex and BMI, the SR-BI -140 to -150del allele was also an independent predictive variable (P=0.041; Table 3) and accounted for 0.5% of the total variance in HDL-C in this population (estimated by R2 change; data not shown). The association demonstrated for the SR-BI -140 to -150del and HDL-C levels was not influenced by sex, obesity, or smoking. Furthermore, no significant difference in plasma HDL-C levels was found between deletion allele carriers compounded with the -142C and -142T alleles (data not shown).
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Effects of SR-BI Gene Promoter -142CT Polymorphism on Plasma Lipid Levels
Table 2 shows the effects of the -142CT polymorphism on plasma HDL-C levels. The SR-BI -142T polymorphism was not significantly associated with plasma HDL-C levels, although subjects with the T allele did tend to exhibit higher HDL-C levels than those with the C allele (P=0.412). There were no significant differences in plasma HDL-C levels between the different genotype groups among males or females, obese or nonobese, or smokers or nonsmokers (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This investigation identified a novel 11-bp deletion mutation and a C
T substitution, located in the promoter region of the SR-BI gene, in a Taiwanese Chinese population. To the best of our knowledge, these are the first 2 mutations identified in the promoter region of the human SR-BI gene. The deletion mutation is an absence of the 11-bp CCCCGCCCCGT in the promoter region (-140 to -150) that covers 1 consensus Sp1 binding site (GCCCCGCCCC). Meanwhile, the other mutation is a CT substitution at position -142, corresponding to the first base of the same Sp1 binding site. The data presented here also strongly suggest that the SR-BI -140 to -150 11-bp deletion is a functional mutation. The luciferase promoter assays demonstrated that the deletion-mutated promoter significantly influenced transcriptional activity. The promoter containing the -140 to -150del allele displayed 32% less activity than that containing the wild-type allele. This observation is consistent with the higher plasma HDL-C levels found in subjects with the deletion allele. Notably, both univariate and multivariate analyses have demonstrated that the SR-BI gene promoter deletion mutation significantly influenced plasma HDL-C levels in this population.
Murao et al14 and Cao et al15 have shown that SR-BI is expressed at high levels in the human liver, adrenal gland, ovary, and testis, which exhibit the bulk of the selective uptake of HDL-C in vivo. Additionally, Acton et al11 found a significant association between the exon 1 SNP and increased HDL-C and decreased LDL-C levels in men, between the exon 8 SNP and reduced LDL-C levels in women, and between the SNP in intron 5 and BMI in women. All of these findings involved a sample group from a Spanish population. The aforementioned finding suggests that SR-BI might also influence the metabolism of both lipoprotein classes in humans. However, it remains unclear whether genetic variants in the promoter region of SR-BI, by affecting SR-BI expression, could significantly influence the interindividual variation of plasma HDL-C levels in humans. The promoter sequences of both human and rat SR-BI genes have already been determined and are very GC-rich, with several important transcriptional regulatory sites in this region.15,16 Moreover, in a study on rats, Mizutani et al16 demonstrated 4 Sp1 binding sites and 3 proximal Sp1 binding sites at positions -102 to -107, -90 to -96, and -48 to -53, which are essential for full promoter activity. Mutations in any 1 of these 3 GC boxes resulted in only 20% to 35% activity compared with the wild-type promoter. Notably, the human SR-BI gene has 5 Sp1 binding sites. Cao et al15 deleted, in stepwise manner, the 5'-flanking sequence of the human SR-BI gene and abolished promoter activity when they removed the fragment from position -182 to -65, which is also the location of the proximal 3 Sp1 binding sites (-142 to -151, -131 to -140, and -119 to -126). Furthermore, Cao et al also identified a steroidogenic factor (SF-1) binding site in this region (-70 to -77) and showed that efficient transcription of the SR-BI promoter in adrenocortical Y1 cells depended on this SF-1 site’s remaining intact. However, the transcriptional factor SF-1 is not expressed in the liver, where SR-BI plays an important role in the reverse cholesterol transport pathway. Overall, this 3-Sp1-binding-site repeat region is believed to be important for SR-BI promoter activity. This work found a naturally occurring mutation characterized by deletion of the third Sp1 binding site upstream from the transcription start site. One report of naturally occurring mutations involving the deletion of 1 or 2 Sp1 binding sites exists, with the deletion occurring in the human 5-lipoxygenase gene promoter region, which normally contains 5 Sp1 binding motifs in tandem.17 Similarly, the mutant promoter of 1 Sp1 binding site deletion in this study also displayed luciferase activity that was reduced by approximately two thirds compared with the wild type. This observation was further confirmed by EMSAs, in which introduction of the -140 to -150del mutant sequence into an oligonucleotide extending from position -164 to -138 disrupted the binding to nuclear protein Sp1. Furthermore, a naturally occurring 1-Sp1-binding-site deletion was associated with significantly raised plasma HDL-C levels. These results suggested that the -140 to -150del mutation was a functional genetic variant and reduced SR-BI gene promoter activity. The -142 CT mutation only involved the edge of the Sp1 site. Sp1 binding on the promoter appeared little affected, with -142T mutant promoter activity and HDL-C levels of subjects with the -142CT polymorphism not being significantly influenced. Therefore, the data presented here suggest that Sp1 might regulate human SR-BI expression in the liver and that subjects carrying the deletion allele might have reduced liver SR-BI expression. Consequently, the plasma HDL-C levels of such subjects were raised owing to decreased selective cholesterol uptake to the liver via SR-BI. Whether this deletion mutation and the CT polymorphism are unique to Taiwanese Chinese or are similarly prevalent in other geographic areas and ethnic groups require confirmation. Moreover, it also remains to be determined whether the association with HDL-C levels can be replicated in other populations.
Epidemiologic investigations have demonstrated an inverse relation between plasma HDL-C levels and the incidence of CHD. However, the absence of SR-BI has been observed to accelerate the onset of atherosclerosis in SR-BI/apolipoprotein E doubly homozygous–KO mice18 and cholesterol-fed, LDL receptor–KO mice,19 whereas atherosclerosis in LDL receptor–KO mice is suppressed by hepatic overexpression of SR-BI,20,21 even with markedly reduced HDL-C levels. Consequently, the relation between the deletion mutation and SNP in the promoter region of SR-BI and risk of CHD deserves further investigation. In conclusion, the findings presented here suggest that genetic variants in the SR-BI promoter region might explain some of the interindividual variation in plasma HDL-C levels in this Taiwanese Chinese population.
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Acknowledgments |
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This study was supported by grants from the National Science Council, Executive Yuan, Taipei, Taiwan, NSC-91–2314-B-182A-059, and by Chang Gung Memorial Hospital Research Program CMRP 1352.
Received March 3, 2003; accepted June 9, 2003.
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