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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:595-599.)
© 1997 American Heart Association, Inc.

Articles

Ser_447stop Mutation in Lipoprotein Lipase Is Associated With Elevated HDL Cholesterol Levels in Normolipidemic Males

Jan Albert Kuivenhoven; Björn E. Groenemeyer; Jolanda M. A. Boer; Paul W. A. Reymer; Riteke Berghuis; Taco Bruin; Hans Jansen; Jacob C. Seidell; ; John J. P. Kastelein

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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Abstract This report describes the association between a frequent mutation in the lipoprotein lipase (LPL) gene and HDL cholesterol levels. It concerns a previously described defect that predicts a premature truncation of the LPL protein (447stop). We determined the frequency of this mutation in three groups of healthy men with low-, middle-, and upper-decile HDL cholesterol. The number of carriers of the 447stop allele was significantly greater in the high HDL group than in either the groups with normal HDL (P=.017) or low HDL (P<.0001). Additional functional assessment of this mutation did not reveal distinct differences between wild-type LPL and the LPL_447stop protein. In conclusion, we have shown that the 447stop mutation is associated with increased HDL cholesterol in healthy Dutch males, although the underlying mechanism remains to be elucidated. Because HDL cholesterol is strongly inversely related with CAD, this genotype might be of potential benefit to its carriers.

Key Words: high-density lipoprotein • lipoprotein lipase • polymorphism • restriction fragment–length polymorphism • coronary artery disease

	Introduction

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Low levels of plasma HDL cholesterol are a strong and independent risk factor for CAD. Several prospective epidemiological studies^{1 2 3} showed a profound inverse relationship between the risk of CAD and plasma HDL cholesterol levels. Recently, these observations were confirmed by experiments with transgenic animals that clearly showed the antiatherogenic properties of this class of lipoproteins.^{4 5 6} Despite intensive research, the mechanism(s) by which HDL exerts its protective function against atherosclerosis is largely unknown. The absence of an apparent increased risk for atherosclerotic disease in persons with low⁷ or even absent plasma HDL cholesterol⁸ highlights the necessity of a better understanding of HDL metabolism and the antiatherogenic potential of this lipoprotein fraction.

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 CETP^{10 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 activity^{20 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 studies^{23 24 25 26} are confusing, and to date, the mechanism by which LPL_447stop 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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Subjects
Men with low, median, and high HDL cholesterol were selected from the Monitoring Project on Cardiovascular Disease Risk Factors that has been performed in the Netherlands since 1987. This project was described in detail by Verschuren et al.³¹

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 diseases—diabetes 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 B–containing 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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Characteristics of Population Samples With Low, Normal, and High HDL Cholesterol
Sufficient DNA was isolated from samples of 98 men with low plasma HDL cholesterol (group A), 70 with normal HDL cholesterol (group B), and 73 with high HDL cholesterol (group C). Table 1 summarizes lifestyle parameters, clinical features, lipids, and lipoproteins of the men included. The three groups were well matched for TC, age, BMI, systolic blood pressure, inactivity, and alcohol consumption. However, although the groups were not statistically different, there was a tendency toward a lower BMI, a lower percentage of inactivity, and a higher percentage of alcohol consumers with increasing HDL. Further analysis of the lifestyle and clinical parameters indicated that men in group C had a significantly lower diastolic blood pressure than men with low plasma HDL cholesterol (P<.05).

View this table: [in this window] [in a new window]   Table 1. Lipids, Clinical Features, and Lifestyle Parameters

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).

View this table: [in this window] [in a new window]   Table 2. Distributions of the 447stop Allele

	Discussion

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To investigate the genetic contribution to plasma HDL cholesterol variability, we defined three groups in which HDL cholesterol was either low, normal, or high. Individuals in these groups were matched for a number of environmental factors and lifestyle parameters known to affect HDL cholesterol levels. Interestingly, the selected samples could not be entirely matched for BMI, alcohol consumption, and inactivity, which indicates the strong effect of these factors on plasma HDL cholesterol levels. Using these population samples, we now report the association between a variant of the gene coding for LPL and plasma HDL cholesterol levels. This variant concerns a nucleotide substitution in exon 9 of the LPL gene that results in the introduction of a stop codon at position 447 (447stop) in the mature protein.¹⁴ Specifically, we showed a significant increase in the number of carriers of the 447stop allele when comparing men with low (8%), normal (19%), and high (40%) HDL cholesterol, respectively. Thus, this variant of LPL may be beneficial through its influence on HDL cholesterol levels. By contrast, Zhang et al³⁰ recently reported the absence of an effect of the 447stop mutation on HDL cholesterol in white subjects who were recruited from cardiac clinics. These differential findings could be related to the vast differences in the population samples studied. Zhang et al³⁰ included large numbers of smokers (75%) and hypertensive subjects (43%). In contrast, we excluded current smokers and subjects with hypertension and further accounted for other factors that are known to affect HDL cholesterol levels.

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 LPL_447stop 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 LPL_447stop 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 LPL_447stop compared with wild-type LPL (measured against triolein⁴² ), which is in agreement with findings of other investigators.^{24 26} The finding that LPL_447stop 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 LPL_447stop 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 LPL_447stop) 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 LPL_447stop 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

 

apo = apolipoprotein BMI = body mass index CAD = coronary artery disease CETP = cholesteryl ester transfer protein LCAT = lecithin:cholesterol acyltransferase LPL = lipoprotein lipase PCR = polymerase chain reaction TC = total cholesterol TG = triglycerides

	Acknowledgments

 
Jan Albert Kuivenhoven was supported by a grant of the Dutch Heart Foundation (R94100). Dr Kastelein is a clinical investigator of the Dutch Heart Foundation. We wish to gratefully acknowledge Drs P.H. Pritchard and M.R. Hayden for their critical suggestions regarding our study and our manuscript. Furthermore, we would like to thank Elianne van der Graaf, Harold Smalheer, and Gert-Jan Botma for their assistance in performing the analyses and Anneke Blokstra for performing the selection and matching of the population samples.

Received January 30, 1996; accepted July 14, 1996.

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