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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2837-2842.)
© 1997 American Heart Association, Inc.

Articles

Common C-to-T Substitution at Position -480 of the Hepatic Lipase Promoter Associated With a Lowered Lipase Activity in Coronary Artery Disease Patients

Hans Jansen; Adrie J. M. Verhoeven; Lilian Weeks; John J. P. Kastelein; Dicky J. J. Halley; Ans van den Ouweland; J. Wouter Jukema; Jaap C. Seidell; ; Jan C. Birkenhäger

From the Departments of Internal Medicine III (H.J., L.W., J.C.B.), Biochemistry (H.J., A.J.M.V.), and Clinical Genetics (D.J.J.H., A. van den O.), Erasmus University Rotterdam; the Department of Molecular Medicine, Academic Medical Center, University of Amsterdam (J.J.P.K.); the Department of Cardiology, University of Leiden (J.W.J.); and the Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven (J.C.S.), The Netherlands.

Correspondence to Hans Jansen, PhD, Department of Internal Medicine III, BD 277, Erasmus University Rotterdam, Dr Molewaterplein 50, 3015 GD Rotterdam, POB 1738, 3000 DR Rotterdam, The Netherlands. E-mail jansen{at}bc1.fgg.eur.nl

	Abstract

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Abstract We studied the molecular basis of low hepatic lipase (HL) activity in normolipidemic male patients with angiographically documented coronary artery disease (CAD). In 18 subjects with a lowered HL activity (<225 mU/mL), all nine exons of the HL gene and part of the promoter region (nucleotides -524 to +7) were sequenced. No structural mutations in the coding part of the HL gene were found, but 50% of the subjects showed a C-to-T substitution at nucleotide -480. Screening for the base substitution in 782 patients yielded an allele frequency of 0.213 (297 heterozygotes, 18 homozygotes). In a group of 316 nonsymptomatic control subjects, the allele frequency was 0.189, which is significantly less than in the CAD patients (P=.035). In the CAD patients, the C-to-T substitution was associated with a lowered lipase activity (heterozygotes -15%, homozygotes -20%). The patients were divided into quartiles on the basis of HL activity. Sixty percent (allele frequency 0.32) of the patients in the lowest quartile (HL activity <306 mU/mL) had the gene variant against 27% (allele frequency 0.14) in the highest quartile (HL activity >466 mU/mL). In the noncarriers, but not in the carriers, HL activity was related with plasma insulin, being increased at higher insulin concentration. Homozygous carriers had a significantly higher HDL cholesterol level than noncarriers (1.13±0.28 mmol/L versus 0.92±0.22 mmol/L, P<.02). Our results show that a C-to-T substitution at -480 of the HL promoter is associated with a lowered HL activity. The base substitution, or a closely linked gene variation, may contribute to the variation in HL activity and affect plasma lipoprotein metabolism.

Key Words: hepatic lipase • promoter • polymorphism • deficiency • coronary artery disease

	Introduction

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Hepatic lipase is a lipolytic enzyme that is synthesized in parenchymal liver cells, secreted, and bound extracellularly to the liver.^{1 2} The enzyme is involved in the metabolism of several lipoproteins.^{3 4} Hydrolysis of phospholipids and triglycerides in HDL under influence of HL may induce cholesterol (ester) flux to the lipase-containing tissues.^{5 6 7 8} During this process, HDL species are formed, which can again take up cholesterol from peripheral tissues.^{5 9} In this way, HL may be an important element in reverse cholesterol transport. HL is also involved in postprandial lipid transport. Inhibition of HL activity in rats by specific antibodies leads to impairment of chylomicron (-remnant) clearing.¹⁰ HL may influence chylomicron-remnant removal via several mechanisms. Hydrolysis of chylomicron-remnant phospholipids by HL leads to the unmasking of apoE, thereby enhancing the binding of the particles to apoE-recognizing receptors.¹¹ In addition, it has been suggested that HL acts as a ligand protein for chylomicron-remnant binding to the liver.^{12 13} HL, besides being present in the liver, is also present in adrenals and ovaries, where it may play a role in cholesterol homeostasis.^{14 15 16} In these tissues, the HL gene is expressed into two products, the full-length mature liver-type lipase and a truncated intracellular protein with unknown function.¹⁷ Altogether, HL seems to be an important enzyme with multiple functions. Nevertheless, deficiency of HL is not easily recognized. HL deficiency leads to elevation in HDL and/or increase in LDL concentration and buoyancy.^{18 19 20 21} In conjunction with other hyperlipidemia-causing genes, HL deficiency influences plasma lipoprotein levels more strongly, leading to triglyceride enrichment of lipoprotein fractions with a density >1.006 g/mL, the presence of ß-VLDL, and an impaired metabolism of postprandial triglyceride-rich lipoproteins.²² A lowered HL activity seems to be associated with an increased atherosclerotic risk. In subjects with HL deficiency, premature atherosclerosis was described.²¹ Normolipidemic subjects with severe atherosclerosis were found to have a lowered activity.^{23 24} A direct relation between HL activity and atherosclerosis was described in a study in coronary heart disease patients on a vegetarian diet, in whom HL activity was found to be inversely correlated with progression of coronary stenosis.²⁵

HL is a member of the lipase gene family.²⁶ It is highly homologous with another member of this family, LPL, and has many characteristics in common. The LPL gene shows a large variation with many mutations affecting LPL gene expression.^{27 28} Although several mutations in the HL gene are described,^{20 29 30} relatively little is known about the role of HL mutations in the variable expression of the HL gene. The phenotype of HL deficiency is often mild and variable. Therefore, candidates for HL deficiency are not easily detected. In addition, HL activity, by which potential HL-deficient subjects could be identified, is not routinely determined. The present study was designed to investigate whether mutations in the coding part of the HL gene generally contribute to low lipase activity in CAD patients. To this end, we sequenced all nine exons of the HL gene in 18 subjects with a well-documented low HL activity. No mutations in any of the exons were found, but we found a frequent C-to-T base substitution in the HL promoter. The association of the polymorphism with HL activity and plasma lipid levels was further investigated in a group of normolipidemic patients with CAD and control subjects.

	Methods

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Study Populations
Coronary artery disease patients were participants of REGRESS and have been described in detail elsewhere.³¹ Briefly, in REGRESS a total of 885 male CAD subjects were included. After a wash-out period of 6 weeks for bile sequestrants and 12 weeks for HMG-CoA reductase inhibitors, patients who were symptomatic for CAD were included. At baseline, each subject had to have at least one coronary artery with a stenosis >50%, as well as a qualifying baseline blood total cholesterol of 4 to 8 mmol/L (155 to 310 mg/dL) and triglycerides <4 mmol/L (350 mg/dL). Patients older than 70 years at entry or who were unable or refused to undergo repeated coronary arteriography were excluded from the study, as were patients with obvious life-threatening illness. REGRESS was conducted under the auspices of the Interuniversity Cardiology Institute of The Netherlands. The study was approved by the ethics committee of each of the participating institutions. Written informed consent was obtained from each patient. Blood samples for lipid and lipase determinations used in the present study were taken at baseline, before study medication was started. A group of 316 unrelated males was used to asses the frequency of the HL promoter polymorphism in non-CAD subjects. General information of the population has been described.³² To match for the REGRESS population, extra selection criteria were used: Dutch nationality; a total serum cholesterol level between 4 and 8 mmol/L; no diabetes mellitus; no history of cerebrovascular disease, myocardial infarction, coronary bypass, or other heart surgery; no history of cancer; no medication for hypertension or hypercholesterolemia; no anticoagulants; a body mass index <33.9 kg/m²; and daily alcohol consumption of maximally three glasses.

DNA Analysis
Subjects for direct sequencing of the HL gene were selected by the presence of a low HL activity (<225 mU/mL) and normal LPL activity (>75 mU/mL) found on two distinct occasions.

Genomic DNA was isolated from leukocytes by standard procedures.³³ All nine exons and part of the HL promoter region (-524 to + 7) were sequenced. Primers (Pharmacia LKB) for amplification were designed on the basis of the HL gene nucleotide sequence by Cai et al³⁴ (Table 1). Sequencing was carried out by using an ALF sequencer (Pharmacia LKB). PCR was carried out in a volume of 100 µL with 10 µL of PCR buffer (GIBCO-BRL) in the presence of 1.5 mmol/L MgCl₂; 0. 1 mmol/L each primer; a mix of 0.8 mmol/L dATP, dGTP, dTTP and dCTP; 0.2 mmol/L spermidine; and 2 U Taq polymerase (GIBCO-BRL). Thermal cycling conditions were 5 minutes at 95°C, followed by 30 cycles of 30 seconds at 95°C, 30 seconds at 52°C, 90 seconds at 72°C, with a final elongation step of 10 minutes at 72°C. Under these conditions, a PCR product of 319 bp is generated. A C-to-T substitution at nucleotide -480, introducing a new Nla III restriction site, was confirmed by restriction analysis. PCR product (10 µL) was digested for 3 hours with 2.5 U Nla III (New England Biolabs). Electrophoresis was performed on a 3% agarose gel containing ethidium bromide. The wild-type PCR product not containing an Nla III restriction site yields a 319-bp band; the heterozygotes, bands of 319, 253, and 66 bp; and the homozygotes, bands of 253 and 66 bp. Allele-specific oligonucleotide hybridization (ASO) was used to assess the frequency of the C-to-T substitution. PCR product (50 µL) was denatured with 100 µL 0.4 mol/L NaOH. From this mixture, 2x70 µL was blotted on Hybond-N+ membrane (Amersham) using the Minifold II slot-blot apparatus (Schleicher & Schuell). The oligonucleotide probes for the ASO technique complementary to -473 to -487 were BHLp2SB (5' -CAC CCC CAT GTC AAA -3') for the C-to-T substitution and BHLp2SA (5' -CAC CCC CGT GTC AAA -3') for the wild-type sequence, respectively. Hybridization was performed at 37°C for 60 minutes. Filters were washed with 0.3 SSC for 10 minutes. The ASO oligonucleotides were labeled using [-³²P]ATP from Amersham and polynucleotide kinase from Boehringer Mannheim.

View this table: [in this window] [in a new window]   Table 1. Primers and PCR Conditions

Lipase Assays
Samples for lipase assays were collected after the IV injection of 50 IU of heparin per kilogram body weight. Fifteen to twenty minutes later, blood was collected from the contralateral arm in ice-cooled heparin-containing tubes. The plasma was separated by low-speed centrifugation and kept frozen until use. The lipases were determined separately by an immunochemical method essentially as described by Huttunen et al,³⁵ using a gum acacia–stabilized [³H]trioleoylglycerol substrate. HL activity was determined as the salt-resistant lipase in the presence of 1 mol/L NaCl. Lipoprotein lipase activity was determined after inhibition of HL with a goat antibody raised against HL purified from postheparin human plasma. The extraction efficiency of [³H]free fatty acids liberated from the substrate during the assay was accounted for by [¹⁴C]oleate added to the substrate as an internal standard. In each series of determinations, pooled plasmas with high and low LP and HL activity were included as a reference. Activities are expressed as milliunits, 1 mU representing the release of 1 nmol fatty acid from the substrate in 1 minute.

HL protein was determined by using a sandwich ELISA technique. Microtiter plates (96 wells, Greiner) were coated with 50 µl per well of a rabbit anti-HL IgG preparation (0.36 mg/mL) in a buffer containing 0.1 mol/L NaHCO₃, pH 9.6, during 2 hours at 30°C. After coating, the wells were incubated with 150 µl 1%(wt/vol) bovine serum albumen in PBS (0.15 mol/L NaCl and 0.1 mol/L NaH₂PO₄, pH 7.2) at room temperature. The wells were washed three times with 150 µl PBS containing 0.1% Tween 20 (PBT). Fifty microliters each of plasma samples, a pool of postheparin plasma, and a pool of heparinized preheparin plasma samples were added to the wells in a 1:50 dilution in PBS and incubated for 2 hours at 30°C. After incubation, the wells were washed three times with 150 µl PBS. A goat anti-human HL IgG served as the second antibody. Fifty microliters of this antibody (1.36 mg/mL) was added to the wells and incubated overnight at 4°C. The plates were washed three times with PBT. Fifty microliters of a swine anti-goat peroxidase preparation (Tago Inc) was added in a 1:1000 dilution in PBS. After incubation for 1 hour at 30°C, 50 µl of a substrate solution was added and reacted for 30 minutes at room temperature in the dark. The reaction was stopped by the addition of 50 µl 2.25 mol/L H₂SO₄, and absorption was read with a Bio-Rad microplate reader. The absorbencies of the postheparin plasma samples were corrected for the absorption of the wells with preheparin plasma. A standard curve of the postheparin pooled plasma was constructed. The amount of HL in the pooled plasma had been determined by comparison with a homogeneity-purified HL preparation from postheparin human plasma, of which protein was determined by the method of Lowry et al.³⁶ The pooled plasma contained 23.6 µg/mL HL protein and 399 mU/mL HL activity. The specificity of the ELISA was tested by application of a postheparin plasma sample of a patient with HL deficiency.¹⁹ With this plasma, no immune reactivity was obtained (not shown). The antibody preparations used were raised against HL purified to homogeneity from postheparin plasma of healthy volunteers, essentially as described by Jensen and Bensadoun.³⁷ The goat antibody was passed over a Sepharose column to which human serum albumen was coupled. Intra-assay variation was 6.8%. Interassay variation was 11.2%.

Analytical Methods
Blood samples were obtained from patients after an overnight fast. Total cholesterol, triglycerides, and HDL cholesterol were measured by standard techniques. Total cholesterol and triglycerides were determined with enzymatic kits (Boehringer Mannheim and Bayer/Technicon, respectively). HDL cholesterol was determined after precipitation of the apoB-containing lipoproteins by 4% tungstate.³⁸ LDL cholesterol was calculated by the formula of Friedewald et al.³⁹ In some of the patients, HDL₂ and HDL₃ were determined by dextran sulfate precipitation⁴⁰ and lipoproteins were separated by sequential ultracentrifugation.⁴¹ Insulin was determined by radioimmunoassay (INS-RIA-100, Medgenix).

Statistical Analysis
Data are presented as mean±SD. Differences between groups were evaluated for significance by using the unpaired Student's t test or by ANOVA followed by the Bonferroni test for comparison of groups. Correlations between variables were calculated using the Pearson correlation test. The difference in allele frequency of the C-to-T substitution between control subjects and CAD patients was tested with the Pearson ² test. The level of significance was set at P<.05.

	Results

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Studies in Subjects With Low HL Activity
Eighteen subjects with CAD with a low HL activity were selected on the basis of their HL activity, determined on at least two separate occasions to be <225 mU/mL. In the whole REGRESS population, the mean HL activity was 387±113 mU/mL (control subjects, 377±116 mU/mL [n=54]). To exclude subjects in which low HL activity might be due to a nonoptimal heparin injection, LPL activity >75 mU/mL (control subjects, 133±46 mU/mL) was a second selection criterion. Mean HL and LPL activities in the selected subjects are given in Table 2. After determining the lipase activity, we determined the HL mass by ELISA. The specific activity, expressed as milliunits lipase activity per µg HL protein in the low-lipase group, was compared with that of 18 patients, matched for LPL activity and age, with a relatively high HL activity (>380 mU/mL). The specific HL activity was similar in the low- and high-lipase groups and not different from the specific activity in 61 CAD patients with HL activity ranging from 72 to 496 mU/mL (mean 325±125 mU/mL) and HL mass ranging from 4.0 to 31.4 µg/mL (mean 20.6±7.25 µg/mL; specific activity 15.7±2.6 mU/µg), indicating that the low lipase activity was not due to structural variations in the HL protein. Low HL was associated with a high HDL₂ cholesterol concentration (Table 2) and an increased cholesterol/triglyceride molar ratio in the VLDL fraction (0.59±0.17 versus 0.47±0.12, P=.03). No differences between the groups were found in other lipoprotein fractions (not shown). Sequencing all nine exons of the HL gene in the low HL patients showed no gene variants, except for an earlier described¹⁸ silent G-to-C substitution in codon 202 in exon 5 in 7 patients. Therefore, we sequenced also part of the HL promoter region (nucleotide -524 to +7). In 9 of the 18 subjects, a C-to-T substitution at position -480 was observed in comparison with published base sequences.^{26 34 42} The base substitution, which will be indicated as C-T(HL-480), introduced a restriction site for Nla III. Restriction analysis confirmed the sequencing results (not shown).

View this table: [in this window] [in a new window]   Table 2. Characteristics of Patients Selected for HL Gene Analysis

Prevalence of C-T(HL-480) in Subjects With CAD and Control Subjects
To determine the prevalence of the C-to-T substitution, an ASO hybridization assay was developed. The assay was applied to 782 patients from the REGRESS population and 316 nonsymptomatic control subjects. Forty percent of the CAD patients were carriers of the C-T(HL-480) substitution (Table 3). In the nonsymptomatic control subjects, 34% were carriers. There was a near significant difference in the amount of carriers and noncarriers between the groups (P=.053). The prevalence of alleles with the C-to-T substitution was significantly higher in the CAD patients than in control subjects (P=.035; Table 3).

View this table: [in this window] [in a new window]   Table 3. Prevalence of C-T(HL-480) in Normolipidemic CAD Patients and Control Subjects

Association Between C-T(HL-480) and HL Activity
The association between the promoter polymorphism and HL activity was studied in the CAD patients. Subjects containing the C-to-T substitution had a significantly lower lipase activity than the wild-type subjects (Table 4). Lipoprotein lipase activity was not significantly different between carriers and noncarriers. To study the relation between the presence of C-T(HL-480) and HL activity more closely, the patients were divided into quartiles on the basis of HL activity. In the quartile with the lowest lipase activity, 60% of the patients had the gene variant. In the quartile with the highest HL activity, only 26% of the subjects were carriers (Fig 1).

View this table: [in this window] [in a new window]   Table 4. HL and LPL Activities (mU/mL) in Subjects With or Without C-T(HL-480)

View larger version (16K): [in this window] [in a new window]   Figure 1. Allele frequency of an HL promoter variant, C-T(HL-480), in relation to HL activity. Quartiles were composed on the basis of HL activity. The allele frequency of the gene variant in each quartile is given. The number of C-T(HL-480) carriers and noncarriers in each quartile is given in the figure (carriers/noncarriers).

Interaction of C-T(HL-480) With Plasma Insulin
The interaction between insulin level and C-T(HL-480) was studied. Quartiles were formed on the basis of plasma insulin. HL activity in C-T(HL-480) carriers and noncarriers in each quartile was calculated. HL activity increased significantly with insulin in the noncarriers (Table 5). In the C-T(HL-480) carriers, no differences in HL activity between any of the quartiles with different insulin were found. In the noncarriers, HL activity was correlated with plasma insulin (P<.001), while in the carriers there was no correlation (P=.24).

View this table: [in this window] [in a new window]   Table 5. HL Activity in Relation to Plasma Insulin (µU/mL) in CAD Patients With or Without C-T(HL-480)

Association Between C-to-T Substitution and Plasma Lipids
We also studied the relation between C-T(HL-480) and plasma lipids (Table 6). Neither cholesterol, triglyceride, nor LDL cholesterol was different between subjects with or without the gene variant. However, HDL cholesterol was significantly higher in subjects homozygous for C-T(HL-480) in comparison with the wild-type patients (Table 6). If the subjects were divided into groups on the basis of HDL cholesterol, the allele frequency of C-T(HL-480) increased with increasing HDL cholesterol (Fig 2). In subjects with an HDL cholesterol <1.11 mmol/L, the allele frequency was significantly lower than in subjects with HDL >1.11 mmol/L (P=.039).

View this table: [in this window] [in a new window]   Table 6. Plasma Lipids and Lipoproteins in CAD Patients With or Without C-T(HL-480)

View larger version (17K): [in this window] [in a new window]   Figure 2. Allele frequency of C-T(HL-480) in relation to HDL cholesterol. The number of C-T(HL-480) carriers and noncarriers in each HDL group is given in the figure (carriers/noncarriers).

	Discussion

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In this study, we describe a C-to-T substitution in the HL promoter region, which is strongly associated with a lowered HL activity. The polymorphism was present in about 40% of patients with angiographically established coronary artery disease and in about 34% of nonsymptomatic control subjects. The C-to-T allele was significantly more frequent in the patients with CAD than in the control subjects. Over 60% of subjects with a low lipase activity were found to contain this gene variation, in contrast to only 27% of the subjects with a relatively high HL activity. The presence of the polymorphism affected HL mass to the same extent as HL activity, so that the specific activity of the enzyme was not affected. These data indicate that either the base substitution itself or a closely linked gene variation influences the expression of the HL gene into enzymatically active HL. In a small group of subjects with low lipase activity, we found no linkage of the promoter variant with mutations in the exons or in the first 524 bp of the HL promoter. Although this finding does not exclude the involvement of other gene variations, it suggests that the base substitution may lead to a lowered HL expression. The gene variant lies in a region that greatly affects promoter activity. Hadzopoulou-Cladaras and Cardot⁴³ showed that elongation of an HL promoter CAT construct next to this region leads to a 61% drop in promoter activity. This observation indicates that alterations in this promoter region may affect HL expression. While the promoter variant is frequently present in patients and control subjects, we found no structural mutations in the coding part of the HL gene in a carefully selected group of CAD patients with low HL activity. Knudsen and coworkers²⁰ described recently a large variation in the coding sequences of the HL gene in a Finnish population. It may be that this apparent discrepancy between our results and theirs arises from the populations studied. Of interest is the apparent interaction of insulin with the expression of C-T(HL-480). Induction of HL activity by insulin is blunted in carriers of the C-to-T polymorphism. How this insulin effect is mediated is not clear, but it suggests that the expression of C-T(HL-480) on HL activity may be influenced by the insulin concentration. We studied the patients after an overnight fast. It may be that if plasma insulin is high, such as during feeding or insulin resistance, HL activity in the noncarriers is more induced than in the carriers. Therefore, under such conditions, the difference in HL activity between carriers and noncarriers may be more pronounced. HL plays a role in HDL metabolism.^{1 2 3 4 5 44 45} Low HL is generally associated with high HDL cholesterol levels and especially HDL₂ cholesterol.^{44 45} This relation between low HL activity and high HDL₂ was also apparent in the subjects with low HL activity that we selected for the present study. Therefore, the higher HDL cholesterol concentration in homozygous C-T(HL-480) carriers in comparison with noncarriers and the association of the C-to-T variant with increased HDL cholesterol were not unexpected. The clinical implications are not clear. From epidemiological studies, it is known that a high HDL cholesterol may protect against premature atherosclerosis. However, we found that the gene variant is more frequently present in subjects with CAD than in nonsymptomatic control subjects, suggesting an opposite effect. It has been shown before that HL deficiency is associated with atherosclerosis even if HDL cholesterol is elevated.^{21 22} Possibly, the influence of a low HL on other lipoproteins outweighs its effect on HDL in terms of atherosclerotic risk.

	Selected Abbreviations and Acronyms

 

CAD = coronary artery disease ELISA = enzyme-linked immunosorbent assay HL = hepatic lipase LPL = lipoprotein lipase PCR = polymerase chain reaction REGRESS = Regression Growth Evaluation Statin Study

	Acknowledgments

 
This study was sponsored in part by the Dutch Heart Foundation. We would like to thank all members of the REGRESS study group for their contribution. Jorien Witte is thanked for help in the development of the ASO assay. Dr Gert-Jan Botma is thanked for help during preparation of the manuscript.

	Footnotes

 
Presented in part at the 66th Congress of the European Atherosclerosis Society, Florence, Italy, July 13-17, 1996.

Received August 28, 1996; accepted March 12, 1997.

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