Articles |
From the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Netherlands (J.A.K, B.E.G., P.W.A.R., R.B., T.B., J.J.P.K.); the Department of Chronic Diseases and Environmental Epidemiology (J.M.A.B., J.C.S.), National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands; and the Departments of Internal Medicine III and Biochemistry (H.J.), Erasmus University Rotterdam, Netherlands.
Correspondence to J.A. Kuivenhoven, Academic Medical Center, Department of Vascular Medicine (G1-114), Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. E-mail: kuif{at}wnet.bos.nl.
| Abstract |
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Key Words: high-density lipoprotein lipoprotein lipase polymorphism restriction fragmentlength polymorphism coronary artery disease
| Introduction |
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Environmental factors that affect plasma HDL cholesterol levels include cigarette smoking, BMI, physical activity, use of ß-blockers and anabolic steroids, alcohol consumption, and oral contraceptives. Conversely, an apparently strong genetic influence on plasma HDL cholesterol levels exists. Defects in the genes coding for CETP, LCAT, apo A-I, and LPL can underlie large changes in HDL cholesterol levels. In general, however, functional defects of these genes are rare in the population and mostly concern only small numbers of patients. By contrast, functional defects in the genes coding for LPL9 and CETP10 11 were recently shown to be relatively frequent and to actually account for significant changes in lipid traits in various population samples.
The vast majority of gene variants described thus far, with the exception of the CETP12 and certain apo E polymorphisms,13 adversely affect lipid and lipoprotein parameters and thereby increase the risk for CAD. By contrast, in this report we describe a common variant of LPL with a putative beneficial effect on plasma HDL cholesterol levels. This variant of the LPL gene was first described by Hata and colleagues.14 The mutation predicts a Ser to stop at position 447 of the mature protein (447stop) that consequently lacks two amino acids at the C-terminus.
Polymorphisms at the LPL gene locus that do not affect the primary structure of the enzyme are more frequently reported to be associated with altered lipid traits, including HDL cholesterol levels.15 16 17 18 19 A positive correlation between HDL cholesterol and LPL activity20 21 is compatible with the concept that LPL-catalyzed hydrolysis of TG-rich lipoproteins will generate surface remnants that contribute to the HDL pool.22 Because the 447stop mutation does alter the primary structure of the LPL protein, several investigators looked for putative functional effects as the result of the premature truncation. However, the results from these studies23 24 25 26 are confusing, and to date, the mechanism by which LPL447stop would raise HDL cholesterol is unknown.
Most of the studies looking for associations between polymorphisms of the LPL gene with plasma TG, HDL cholesterol levels, and the risk of atherosclerosis are case-control studies.15 16 17 18 19 27 28 29 30 Our study, however, is part of a larger study designed to define genetic factors that regulate plasma HDL cholesterol levels in the male population in the Netherlands. We now describe the frequency of the 447stop allele of the LPL gene in the upper, middle, and lower deciles of HDL cholesterol levels occurring in a representative sample of healthy Dutch men.
| Methods |
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For the purpose of the present study, the following exclusion criteria were used: female sex; men >55 years of age; men who were current smokers according to the questionnaire; men who drank >1 alcoholic beverage per day; men who had a BMI >27 kg/m2; the presence or history of any of the following diseasesdiabetes mellitus, cerebrovascular accidents, cancer, and kidney stones; men who were treated for hypertension or hyperlipidemia or received anticoagulants; measured serum TC <3.82 mmol/L (<10th percentile) and TC >6.50 mmol/L; medication known to affect plasma lipids (diuretics, anabolic steroids, ß-blockers, antiepileptics, and barbiturate derivatives); and abnormal dietary habits.
After calculation of percentiles of HDL cholesterol in the remaining population, we defined three groups: (1) HDL cholesterol 0.87 mmol/L (10th percentile; group A); (2) HDL cholesterol between 1.09 and 1.15 mmol/L (45th to 55th percentile; group B); and (3) HDL cholesterol 1.44 mmol/L (90th percentile; group C). We subsequently tried to match these groups for age, BMI, percentage of inactivity in spare time, number of alcoholic beverages consumed per day, plasma TC, and systolic and diastolic blood pressures. Because there were major differences in average BMI between the three resulting groups, these groups were further stratified by BMI (cutoff point of 24.96 kg/m2, which was the median BMI in the low-HDL group). From each of the three groups, 140 men were selected (34 above and 106 below a BMI of 24.96 kg/m2).
Lipid Determinations and DNA Isolation
Plasma TC was determined enzymatically by use of a Boehringer
test kit.32 HDL cholesterol was determined with the same
method after precipitation of the apo Bcontaining lipoproteins with
magnesium phosphotungstate.33 Nonfasting plasma TG levels
were determined enzymatically (Biomerieux). LDL cholesterol was
calculated by use of the Friedewald formula.34 Genomic DNA
was extracted from buffy coats as described
previously.35
PCR-Based Detection of the Stop Allele
We amplified the target sequence of the LPL gene
(terminal part of exon 9) by using 5'-TACACTAGCAATGTCTAGGTGA-3' as
upstream primer and 5'-TCAGCTTTAGCCCAGAATGC-3' as downstream primer.
The amplification reactions were performed in 10 mmol/L Tris-HCl
(pH 9.0), 50 mmol/L KCl, 0.1% wt/vol gelatin, 1.5 mmol/L
MgCl2, 1% Triton X-100, and 0.2 mg/mL bovine serum albumin
containing 0.1 to 0.5 µg genomic DNA and final concentrations of
200 µmol/L dNTPs and 0.5 µmol/L primers in a total volume
of 50 µL. After initial denaturation (10 minutes, 95°C), 1.0 U
thermostable DNA polymerase (Supertaq; HT Biotechnology Ltd) was added,
followed by 30 amplification cycles of 95°C (1 minute), 60°C (1
minute), and 72°C (1 minute) with a final extension step of 10
minutes at 72°C. Twenty percent of the PCR reaction product was used
for digestion with 3 U Mnl I according to the instructions
of the manufacturer (New England Biolabs) in a total volume of 20 µL
for 2 hours at 37°C. After electrophoresis of the PCR product in 3%
agarose containing ethidium bromide, DNA restriction fragments were
visualized and analyzed on a transilluminator.
Statistical Analysis
All subjects selected for this study were categorized according
to their HDL cholesterol levels as described previously. Means were
compared between groups with the use of ANOVA. The Tukey test was
performed to adjust for multiple comparisons. Categorical variables
were compared with the use of a
2 test. All
statistical analyses were performed with the Statistical Analysis
System (SAS version 6.1, SAS Institute). Values of P<.05
were considered statistically significant.
| Results |
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Regarding lipid values, the statistically significant decrease in TG levels found in comparisons of groups A and B and B and C, respectively (P<.05), clearly illustrates the inverse correlation between plasma HDL cholesterol and TG levels.
Distributions and Frequencies of the Stop Allele
Using PCR-based DNA analysis, we identified significant
differences in the frequency of the 447stop allele in the three groups
investigated (Table 2
). The increase in the number of
carriers of this mutation in group B compared with group A almost
reached statistical significance (P=.058). Furthermore,
there was a significant increase of carriers in group C compared with
group B (P=.017). Finally, when group A was compared with
group C, the "overrepresentation" of the 447stop allele in men
with high plasma HDL cholesterol was highly significant
(P<.0001).
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| Discussion |
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The 447stop allele frequency in our sample with normal HDL cholesterol levels was similar to that reported by others.19 24 However, some investigators identified higher14 and lower29 frequencies of this polymorphism, which might be related to differences in sample selection, the ethnic origin of the populations studied, and selection criteria used to define control subjects.
The mechanism by which this variant of the LPL protein exerts its HDL cholesterol-raising effect could be related to enhanced lipolytic activity. This explanation is biologically plausible because a higher lipolytic activity would result in a decrease in TG levels and an increase in the transfer of protein, phospholipid, and cholesterol from VLDL particles to HDL3 particles, resulting in an increase in HDL2 (the main determinant of variations in total HDL cholesterol concentration) levels according to evidence provided by Patsch et al22 and Nikkilä et al.36 Furthermore, the correlation between postheparin LPL activity and HDL2 cholesterol concentration is well established under several clinical conditions.37 38 39 40 For example, Nikkilä et al38 observed a strongly positive correlation between postheparin lipolytic activity and HDL cholesterol levels in diabetics treated with insulin. In addition, Kuusi et al21 showed a major influence of both hepatic lipase and LPL on HDL cholesterol levels at the population level in Finland. Postheparin LPL activity in their study was significantly elevated (P<.001) in subjects with high HDL cholesterol compared with subjects with low HDL cholesterol. The need for more data on the in vivo effects of this LPL447stop variant on lipid traits in normolipidemics is obvious in light of the limited studies performed to date.29
To date, in vitro data on the LPL447stop are equivocal with regard to the actual effect of the premature truncation on LPL function,23 24 25 26 and therefore, we performed functional assessment of this mutation.41 The results indicated an essentially similar specific activity of LPL447stop compared with wild-type LPL (measured against triolein42 ), which is in agreement with findings of other investigators.24 26 The finding that LPL447stop exhibits higher23 or lower25 specific activity could be related to differences in the LPL mass assays used. To further study the aspects that might underlie the association with higher HDL cholesterol, we set out to determine monomer/dimer ratios of both mutant and wild-type LPL, because LPL is mainly active as a dimer. In addition, we determined the stability of the mutant protein compared with the wild type using various methods.43 All these experiments revealed that the LPL447stop and wild-type LPL exhibited similar properties (results not shown).
Given these results, we would like to suggest alternative hypotheses to explain the association between the 447stop mutation and elevated HDL cholesterol. First, the presence of LPL heterodimers (composed of both wild type and LPL447stop) in heterozygous carriers of the 447stop mutation might be more stable than dimers composed of wild-type monomers. Second, in vitro studies do not include the effects of the "natural" genetic environment, including the endogenous promoter, of the LPL gene. Finally, one could argue that the 447stop mutation is in linkage disequilibrium with another defect in the LPL gene that could be associated with the identified phenotype. In this view, we screened the LPL gene of seven 447 carriers for additional sequence variations. However, using denaturation gradient gel electrophoresis of LPL gene fragments that covered all coding sequences (and 500 base pairs of the promoter region), we could not identify other LPL defects in these subjects. On the basis of these results, we still cannot rule out the possibility that the 447stop mutation is in linkage disequilibrium with a genetic change outside of the sequence investigated. However, this finding does support the idea that the 447stop mutation exerts a direct effect on LPL function, although we were not able to confirm this by our in vitro analysis. In conclusion, our observations clearly indicate the need for additional fundamental studies on the in vivo effects of LPL447stop on HDL cholesterol levels.
Defects of the LPL gene reported thus far are known to adversely affect HDL cholesterol levels. In this respect, heterozygous LPL deficiency was recently suggested to be associated with premature coronary atherosclerosis and reduced HDL cholesterol levels.9 40 44 45 46 By contrast, we showed that heterozygosity for the 447stop mutation of the LPL gene is associated with elevated plasma HDL cholesterol levels. Therefore, one could hypothesize that the presence of the 447stop mutation is of potential benefit to its carriers.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received January 30, 1996; accepted July 14, 1996.
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