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Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:815-822

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:815.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Association of the C-514T Polymorphism in the Hepatic Lipase Gene With Variations in Lipoprotein Subclass Profiles

The Framingham Offspring Study

Patrick Couture; James D. Otvos; L. Adrienne Cupples; Carlos Lahoz; Peter W. F. Wilson; Ernst J. Schaefer; Jose M. Ordovas

From the Lipid Metabolism Laboratory (P.C., C.L., E.J.S., J.M.O.), Jean Mayer–USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Mass; the Department of Biochemistry (J.D.O.), North Carolina State University, Raleigh; Boston University School of Public Health (L.A.C.) and the Framingham Heart Study (P.W.F.W.), National Heart, Lung, and Blood Institute, Framingham, Mass.

Correspondence to Dr Jose M. Ordovas, Lipid Metabolism Laboratory. Jean Mayer–USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St, Boston, MA 02111. E-mail ordovas{at}hnrc.tufts.edu


*    Abstract
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Abstract—Hepatic lipase is involved in the metabolism of several lipoproteins and has a key role in reverse cholesterol transport. A common C-to-T substitution at position -514 of the hepatic lipase promoter has been associated with variations in plasma high density lipoprotein cholesterol (HDL-C) levels and hepatic lipase activity. The aim of the current study was to investigate the association of this polymorphism to lipoprotein levels in a population-based sample of 1314 male and 1353 female Framingham Offspring Study participants. In men and women, carriers of the -514T allele had higher HDL-C and apolipoprotein A-I (apoAI) concentrations compared with noncarriers. The higher HDL-C levels associated with the -514T allele was due to an increase in the HDL2-C subfraction, and this association was stronger in women compared with men (P=0.0043 versus 0.0517). To gain further understanding about the metabolic basis of these effects, HDL and low density lipoprotein (LDL) subclass profiles were measured by using automated nuclear magnetic resonance spectroscopy and gradient gel electrophoresis, respectively. The association of the -514T allele with higher HDL-C levels seen in men and women was primarily due to significant increases in the large HDL subfractions (size range 8.8 to 13.0 nm). In contrast, there was no relationship between the hepatic lipase polymorphism at position -514 and the LDL particle size distribution after adjustment for familial relationships, age, body mass index, smoking, alcohol intake, use of ß-blockers, apoE genotype, and menopausal status and estrogen therapy in women. Moreover, multiple regression analyses suggested that the C-514T polymorphism contributed significantly to the variability of HDL particle size in men and women (P<0.04). Thus, our results show that the C-514T polymorphism in the hepatic lipase gene is associated with significant variations in the lipoprotein profile in men and women.


Key Words: hepatic lipase • HDL • gene polymorphisms • lipoprotein particle size


*    Introduction
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Epidemiological studies have provided strong evidence that a low plasma concentration of HDL cholesterol (HDL-C) is associated with an increased risk of developing coronary heart disease (CHD).1 2 3 Other major CHD risk factors include age, male sex, arterial hypertension, diabetes, smoking, a familial history of premature CHD, and an elevated plasma LDL cholesterol (LDL-C) level.4 5 6 Decreased plasma HDL-C concentrations are clearly associated with environmental variables such as abdominal obesity,7 life style, and cigarette smoking,4 but genetic factors also play a significant role.8 In fact, family and twin studies have shown that genetic polymorphism could account for up to 60% of the interindividual variation in plasma HDL-C concentrations.9 10 11 Recent studies suggest that polymorphisms at the hepatic lipase,11 12 13 apolipoprotein AI/CIII/AIV,11 and cholesteryl ester transfer protein14 loci could be a major cause of genetically determined variation in plasma HDL-C levels.

Hepatic lipase is a lipolytic enzyme that is synthesized in the hepatocytes, secreted, and bound extracellularly to the liver.15 Hepatic lipase participates in the metabolism of IDL and large LDL to form smaller, denser LDL particles and in the conversion of HDL2 to HDL3. In addition, hepatic lipase can mediate the unloading of cholesterol from HDL to the plasma membrane in the liver.16 It has also been suggested that hepatic lipase may act as a ligand protein with cell-surface proteoglycans in the uptake of lipoproteins by cell-surface receptors.15 The lipid profile of individuals with complete hepatic lipase deficiency is characterized by elevated plasma cholesterol and triglyceride levels, 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.17 18 Four polymorphism in the 5'-flanking region of the hepatic lipase gene (G->A at position -250, C->T at -514, T->C at -710, and A->G at -763) with respect to the transcription start site13 were observed to be in complete linkage disequilibrium13 19 and were found to be associated with a lowered hepatic lipase activity and higher HDL-C levels.12 13 20 A number of recent studies have also shown an association between low hepatic lipase activity and more buoyant, less atherogenic LDL particles21 22 and suggest that variants in the hepatic lipase promoter may contribute significantly to the prevalence of the atherogenic small, dense, LDL particle phenotype associated with an increased CHD risk.20 23 24 25

In recent studies, the C-514T polymorphism in the promoter region of the hepatic lipase gene has been shown to be associated with significant variations in hepatic lipase activity, plasma HDL-C levels, and LDL particle size. However, data from the general population with regard to the effect of this common hepatic lipase variant on lipid and lipoprotein levels, as well as the heterogeneity and possible atherogenicity of LDL and HDL lipoprotein particles, are clearly missing. The purpose of the current study, therefore, was to examine the frequency, phenotypic effect on lipoprotein levels and lipoprotein subclass profiles, and the potential modulation of CHD risk in the Framingham Offspring Study (FOS) by the C-514T polymorphism in the hepatic lipase gene.


*    Methods
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Subjects
The details of the design and methods of the FOS have been presented elsewhere.26 Starting in 1971, a total of 5124 subjects were enrolled.27 Blood samples for DNA were collected between 1987 and 1991. Lipid phenotypes, DNA, and information on CHD risk factors were available for 1314 men and 1353 women who attended the third, fourth, and fifth examination visits of the FOS conducted between 1983 and 1995 and who had lipid values available when they were not taking lipid-altering medication. Nearly all subjects were white. Data on smoking, blood pressure, height, weight, and diabetes were obtained on these subjects as previously described.27 28 CHD included the presence of myocardial infarction, angina pectoris, coronary insufficiency, and coronary death. All suspected CHD events were reviewed by a panel of 3 physicians to ascertain the presence of CHD. Subjects taking a lipid-lowering medication were included for the calculation of CHD prevalence at examination 5.

Plasma Lipid, Lipoprotein, and Apoprotein Measurements
Twelve-hour fasting venous blood samples were collected in tubes containing 0.1% EDTA. Plasma was separated from blood cells by centrifugation and immediately used for the measurement of lipids. Plasma total cholesterol, HDL-C, and triglyceride levels were measured as previously described.29 HDL-C was measured after precipitation of apoB-containing lipoproteins with heparin-MnCl2.30 LDL-C concentrations were estimated with the equation of Friedewald et al.31 Coefficients of variation for total cholesterol, HDL-C, and triglyceride measurements were each <5%. Plasma levels of apoAI and apoB were measured by noncompetitive ELISA with the use of affinity-purified polyclonal antibodies.32 33

HDL subclass distributions were determined by proton nuclear magnetic resonance (NMR) spectroscopy as previously described.34 35 Each profile displays the concentrations of 5 HDL subclasses and their weighted-average particle sizes. The 5 HDL lipoprotein subclass categories used were the following: large HDL (8.8 to 13.0 nm), intermediate HDL (7.8 to 8.8 nm), and small HDL (7.3 to 7.7 nm). Levels of HDL subclasses are expressed in units of cholesterol (mg/dL). HDL subclass distributions determined by gradient gel electrophoresis and NMR have also been shown to be closely correlated.34

LDL subclasses were separated by subjecting whole plasma to 2% to 16% gradient gel electrophoresis and were visualized by using Sudan black to stain LDL particles, as previously described.36 37 Each subject was assigned an LDL type, with the largest, LDL1, being found in the density range 1.019 to 1.033 g/mL; LDL2 and LDL3 in the range 1.033 to 1.038 g/mL; LDL4 and LDL5 in the range 1.038 to 1.050 g/mL; and the smallest, LDL6 and LDL7, in the range 1.050 to 1.063 g/mL. Because we found that most of the subjects had 1 major LDL peak and 1 or 2 minor peaks, we estimated the percent relative area of each LDL peak after scanning. To take into consideration the presence of secondary peaks, an LDL score for each subject was calculated as the sum of the relative areas under all LDL peaks present. A smaller LDL particle score corresponds to a larger LDL particle diameter.

DNA Analysis
Genomic DNA was isolated from peripheral blood leukocytes by standard methods.38 Hepatic lipase genotyping was performed as described by Guerra et al.13 A 285-bp sequence of the hepatic lipase gene was amplified by polymerase chain reaction (PCR) in a DNA thermal cycler (PTC-100, M.J. Research, Inc) by using oligonucleotide primers 5'-TCTAGGATCACCTCTCAATGGGTCA-3' and 5'-GGTGGCTTCCACGTGG-CTGCCTAAG-3'. DNA templates were denatured at 95°C for 3 minutes, and then each PCR was subjected to 35 cycles, each consisting of 1 minute of denaturation at 95°C, 0.5 minute of annealing at 63°C, and 0.5 minute of extension at 72°C. The PCR products were digested with 10 U of NlaIII and the fragments separated by electrophoresis on a 1.5% agarose gel. After electrophoresis, the gel was treated with ethidium bromide for 20 minutes, and DNA fragments were visualized by UV illumination. The resulting fragments are 215 and 70 bp for the T allele and 285 bp for the uncut C allele.

Statistical Analyses
To compare men and women who participated in the study, we used {chi}2 tests for categorical measures and a 2-sample t test for continuous measures. We estimated the frequency of both the T and apoE alleles with the chromosome counting method and used a {chi}2 test to compare these frequencies in men and women. To evaluate the relationship between the hepatic lipase genotypes (CC, CT, and TT) and lipid levels, we used ANCOVA techniques, which accounted for the familial relationships among the members of the study (mostly siblings and cousins). We used 2 approaches to accomplish these analyses. First, we employed a repeated-measures approach that assumed an exchangeable correlation structure among all members of a family by using PROC MIXED in the SAS package. Because this approach does not accurately represent the true correlation structure within these pedigrees, we also employed a measured-genotype approach39 as implemented in SOLAR, a variance component analysis computer package for quantitative traits measured in pedigrees of arbitrary size.40 The latter approach fully accounts for the different types of relationships within a pedigree in performing an ANOVA on the defined genotypes. In these analyses, we used several different models to adjust for potential confounders. First, we obtained essentially crude results, which accounted only for the family structure; second, we adjusted for age, body mass index (BMI), smoking, alcohol consumption, use of ß-blockers, and menopausal status and hormonal replacement therapy in women. In our final analysis, we added apoE genotypes to the model, with E2/E2 and E2/E3 in 1 group, E3/E4 and E4/E4 in a second group, and E3/E3 as the reference group. Subjects with the apo E2/E4 genotype, of which there were very few, were excluded.


*    Results
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Subject Characteristics
To investigate the frequency and phenotypic association of the C-514T variants at the population level, we analyzed a total of 2667 subjects (1314 males and 1353 females) who participated in the FOS and who had lipid values available when they were off lipid-altering medication. Table 1Down provides a summary of the demographic, genotypic, and biochemical characteristics of the participants according to sex. The mean age of men and women at examination was 52.2 and 51.3 years, respectively. Although similar proportions of men and women were smokers, male subjects smoked more cigarettes per day than did the female smokers, and over half of the female participants (54.2%) were postmenopausal. There was no significant difference in the frequency of the T allele between men and women, and the distribution of alleles was consistent with Hardy-Weinberg equilibrium. Furthermore, alcohol consumption, BMI, plasma LDL-C, total apoB, and triglyceride as well as glucose levels were significantly higher in men compared with women, and total HDL-C, HDL2-C, and HDL3-C concentrations were significantly higher in female participants. The apoE genotype distribution was similar in men and women (P=0.3980).


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  		Table 1. Demographic, Genotypic, and Biochemical Characteristics of FOS Participants According to Sex

Association of the C-514T Polymorphism With Variations in Plasma Levels of Lipids, Lipoproteins, and Apoproteins
Table 2Down shows that in men and women, the 3 genetic groups were equivalent with respect to age and BMI. However, male and female carriers of a T allele had higher HDL-C and apoAI concentrations compared with noncarriers. The higher HDL-C levels associated with the T allele were due to an increase in the HDL2-C subfraction. Moreover, the association of the T allele with higher HDL2-C levels was stronger in women compared with men after adjustment for familial relationships, age, BMI, smoking, alcohol intake, the use of ß-blockers, apoE genotype, and menopausal status and estrogen therapy in women. In both sexes, there was no significant difference between the genetic groups in the plasma levels of total cholesterol, LDL-C, apoB, and triglyceride. To better understand the metabolic basis of the association of higher HDL-C levels with the T allele in men and women, lipoprotein subclass profiles were measured by automated NMR spectroscopy. As shown in Table 3Down, this association was significant in women only and was primarily due to an increase in the large HDL subfraction.


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  		Table 2. Plasma Levels of Lipids, Lipoproteins, and Apoproteins of FOS Subjects According to Hepatic Lipase Genotypes at Nucleotide -514


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  		Table 3. HDL Subclass Distributions of FOS Subjects According to Hepatic Lipase Genotypes at Nucleotide -514

Association of the C-514T Polymorphism With Variations in Lipoprotein Particle Size
We also investigated the effect of the hepatic lipase variants on HDL and LDL particle size. Overall, the T allele was associated with a significant increase in HDL particle diameter in both men and women (Table 4Down). No significant association was observed between the hepatic lipase polymorphism and LDL particle size (Table 5Down). The association of the T allele with increased HDL particle size was greater in women compared with men after adjustment for familial relationships, age, BMI, smoking, alcohol intake, the use of ß-blockers, apoE genotype, and menopausal status and estrogen therapy in women.


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  		Table 4. HDL Diameters of FOS Subjects According to Hepatic Lipase Genotypes at Nucleotide -514


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  		Table 5. LDL Scores of FOS Subjects According to Hepatic Lipase Genotypes at Nucleotides -514

Hepatic Lipase Genotype and Risk of CHD
CHD was present in 159 men (11.5%, mean age 54.1±10.0 years) and 60 women (4.3%, mean age 53.9±7.6 years). Of the 506 male carriers, 58 had a history of CHD compared with 101 of 875 noncarriers (P=0.3440). In women, 19 of the 509 carriers had a history of CHD compared with 41 of the 886 noncarriers (P=0.7270). Moreover, no significant difference in the age of onset of CHD between carriers and noncarriers was observed in both sexes. In men, carriers of the -514T mutation had a mean age of onset of CHD of 53.8±9.0 years compared with 54.2±10.5 years in noncarriers (P=0.5468), whereas in women, the mean age of onset of CHD was 53.7±7.1 and 54.0±7.8 years for carriers and noncarriers, respectively (P=0.5292). Our analyses showed that no increased risk for CHD could be attributed to this polymorphism.


*    Discussion
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Cardiovascular diseases are a leading cause of death in most industrialized countries, and both genetic and environmental factors have been shown to play an important role in their etiology. Genetic and constitutional factors are known to play an important role in determining interindividual variation in plasma HDL-C levels. In this regard, data from family and twin studies indicate that genetic variations account for between 40% and 60% of the total variation in HDL-C levels.41 42 Using sibling-pair linkage analysis, Cohen et al11 have demonstrated that allelic variation at the hepatic lipase locus accounts for as much as 25% of the variability in plasma HDL-C concentrations. The C-514T polymorphism in the hepatic lipase gene was first reported as the molecular basis of low hepatic lipase activity in normolipidemic male patients with CHD.12 Similar findings were described in several studies that have confirmed the presence of a significant association between this polymorphism and variations in hepatic lipase activity and plasma HDL-C levels.13 19 20 43 44 However, phenotypic expression of this polymorphism in the lipoprotein profile and CHD risk has not been reported in the general population. We report here that {approx}36% of North Americans of white descent may be carriers of this functional polymorphism in the hepatic lipase gene. The carrier prevalence for the C-514T polymorphism in the FOS is thus similar to that reported earlier in white subjects from European countries12 43 44 or the United States in general.13 19 These results are consistent with the ethnic background of the FOS, as the vast majority of participants are descended from Italian, Irish, French, and British immigrants to North America over the last 350 years.

We have also shown that in women, the T variant was associated with higher HDL-C concentrations due to an increase in the large-HDL subfractions. Presumably, these changes in HDL subfraction distribution are a reflection of changes in hepatic lipase activity.12 20 Compared with homozygous CC women, women with the CT genotype at position -514 had 3.1% and 8.5% higher HDL-C and HDL2-C levels, respectively. Furthermore, only plasma HDL2-C concentrations appear to be associated with the hepatic lipase polymorphism, whereas the HDL3-C concentrations are not, suggesting that the HDL particle size distribution rather than total HDL-C may represent a more sensitive marker for testing the effect of the C-514T polymorphism on HDL metabolism. A similar trend was seen in men, although the differences were not statistically significant. The significance of this finding remains to be established, but several lines of evidence have demonstrated that plasma hepatic lipase activity levels and HDL-C concentrations are modulated by a number of exogenous and endogenous factors in addition to the hepatic lipase promoter polymorphisms. These include estrogen levels,45 visceral fat, insulin resistance,46 47 48 and drugs.49 Further studies will be required to assess the sex-dependent relationship between plasma HDL-C and HDL subclass distribution and the hepatic lipase promoter genotype. At least we can speculate that the hepatic lipase genotype may influence the metabolic relationships that determine how HDL particles are metabolized in women. Furthermore, the variance components analysis performed in the FOS participants indicated that the C-514T polymorphism in the hepatic lipase gene accounted for <1% of the variance in plasma concentrations of HDL-C and HDL2-C, indicating that the genetically determined variability in plasma HDL-C and HDL2-C levels is most likely due to allelic variation in a relatively large number of genes, each of which has a small or moderate influence.

In previous studies,12 13 no functional mutations were detected in the coding sequence of the hepatic lipase gene that could account for the observed relationship between hepatic lipase activity, plasma HDL-C levels, and genetic polymorphism of the hepatic lipase promoter. Because we did not measure hepatic lipase activity directly in the FOS participants, we can only speculate on the mechanisms underlying the association between the C-514T polymorphism and variations in plasma HDL-C and HDL2-C concentrations. In fact, it is possible that this polymorphism does not directly affect hepatic lipase expression and HDL-C levels but that another linked polymorphism within the hepatic lipase gene affects its expression. Finally, we cannot exclude the possibility that the C-514T polymorphism is in linkage disequilibrium with another unidentified gene responsible for variations in plasma HDL-C concentrations, but so far, no other genes affecting plasma HDL-C levels have been identified in close proximity to the hepatic lipase locus.

Epidemiological studies have suggested that both small, dense LDL23 24 and low HDL-C1 50 are associated with an increased risk of developing CHD. In fact, the change in LDL particle size appears to be mediated by a complex network of genetic, metabolic, and hormonal factors. The factors associated with decreased LDL particle size include male sex; decreased HDL-C and apoAI levels; elevated triglycerides; low-fat, high-carbohydrate diets; and ß-adrenergic blocker use.23 Thus, it has been suggested that LDL particle size distribution is a marker for a series of metabolic alterations that are probably influenced by similar mechanisms.51 In the current study, the increased HDL particle size associated with the T-514 variant was not associated with smaller, denser LDL particles after adjustment for familial relationships and other covariates. This observation is in contrast with previous studies demonstrating a significant relationship between hepatic lipase promoter polymorphism, hepatic lipase activity, plasma HDL2-C levels, and LDL buoyancy.20 22 52 Differences in the phenotypic expression of the hepatic lipase variants could be related to factors such as sample size, admixture or population stratification, differences in environmental factors, and/or differences in genetic background of the populations studied. It should be noted that different dietary habits across populations may influence the genotype-lipid associations. Moreover, the older age of participants in our study may be responsible, at least in part, for these discrepancies, because as previously indicated, the hormonal profile in women might modulate the effect of the hepatic lipase polymorphism on HDL subclass distribution.

Several studies in humans and animals have yielded conflicting results concerning the potential role of hepatic lipase in the pathogenesis of atherosclerosis.53 Some of the previously described hepatic lipase–deficient individuals have suffered from CHD,18 54 55 but the precise contribution of hepatic lipase deficiency to the presence of CHD may be obscured by the presence of other concomitant lipoprotein disorders.53 Hepatic lipase deficiency results in the elevation of plasma HDL2-C levels, a change that is considered antiatherogenic but that is also associated with the impaired clearance of lipoprotein remnants,17 56 decreased production of pre-ß-HDL,57 and decreased delivery of HDL-C to the liver.15 All these changes are potentially atherogenic. From epidemiological studies, it is known that a low plasma HDL-C level is a major risk factor for CHD1 58 and, consistent with its role in the hydrolysis of triglycerides and phospholipids of HDL, hepatic lipase activity is inversely correlated with HDL-C concentrations.59 60 Thus, it has been hypothesized that the lower hepatic lipase activity and higher HDL-C levels present in premenopausal women would be responsible for their lower risk of heart disease.61 62 Likewise, Blades et al63 have demonstrated that an increase in hepatic lipase activity is the major change in lipolytic enzymes observed in hypoalphalipoproteinemic subjects with or without hypertriglyceridemia. In contrast, several studies have provided evidence for the protective role of hepatic lipase in atherosclerosis. It has been shown that hepatic lipase activity is inversely correlated with the degree of calcific atherosclerosis in patients homozygous for familial hypercholesterolemia.64 Similarly, hepatic lipase activity is significantly reduced in normolipidemic men with CHD, a finding also associated with delayed clearance of postprandial lipoproteins.65 The current study clearly shows that the C-514T polymorphism in the hepatic lipase promoter is associated with significant variations in plasma HDL2-C levels in women and HDL particle size in both sexes, but the cumulative effects of these variations on atherosclerotic risk remain uncertain, probably owing to the small numbers of CHD patients in this young cohort. This underscores the need for larger, prospective studies in the assessment of common genetic polymorphism with mild effects on lipoprotein subclass profiles and outcome such CHD. Consequently, the role of hepatic lipase deficiency in the pathogenesis of CHD remains controversial, and more studies at the population level are needed.


*    Acknowledgments
 
This work was supported by grants HL54776 and HL35243 and NIH/NHLBI contract NO1-38038 and contract 53-K06-5-10 from the US Department of Agriculture Research Service. Dr Couture was supported by a fellowship from Laval University, Québec, Canada. J.D. Otvos is affiliated with Lipomed Inc (Raleigh, NC), which commercializes the use of NMR for measuring lipoprotein particles.

Received April 26, 1999; accepted October 25, 1999.


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 *References
 

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