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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:714-720

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:714-720.)
© 1995 American Heart Association, Inc.

Articles

The Lipoprotein Lipase HindIII Polymorphism Modulates Plasma Triglyceride Levels in Visceral Obesity

Marie-Claude Vohl; Benoît Lamarche; Sital Moorjani; Denis Prud'homme; André Nadeau; Claude Bouchard; Paul-J. Lupien; Jean-Pierre Després

From the Lipid Research Center, CHUL Research Center (M.-C.V., B.L., S.M., P.-J.L., J.-P.D.), the Physical Activity Sciences Laboratory (D.P., C.B.), and the Diabetes Research Unit, CHUL Research Center (A.N.), Laval University, Ste-Foy, Québec.

Correspondence to Dr Jean-Pierre Després, Lipid Research Center CHUL, 2705 Laurier Blvd, Québec, GIV 4G2, Canada.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
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Abstract The aim of this study was to investigate the potential interaction between the lipoprotein lipase (LPL) HindIII polymorphism and visceral adipose tissue (AT) accumulation in the modulation of triglyceride levels in visceral obesity. The LPL-HindIII genotype was determined by polymerase chain reaction in 52 men. Twenty-three subjects were heterozygous (+/-) and 28 were homozygous (+/+) for the presence of the restriction site. One subject who was homozygous for the - allele was excluded from analysis. Body mass index (BMI), fasting insulin level, and visceral AT area as measured by computed tomography were positively correlated with triglyceride levels only in subjects homozygous for the + allele. Furthermore, whereas these variables were negatively correlated with plasma HDL2 cholesterol concentrations in the +/+ group, these associations were not found in +/- heterozygotes, with the exception of BMI. To further investigate the interaction of the LPL-HindIII polymorphism with visceral obesity and hyperinsulinemia, the two genotype groups were further subdivided on the basis of BMI (low versus high), fasting insulin level (low versus high), and visceral AT area (low versus high), and their lipoprotein profiles were compared. Elevated levels of abdominal visceral AT were significantly associated with increased triglyceride concentrations in +/+ homozygous men, suggesting that visceral obesity may lead to hypertriglyceridemia in the presence of the +/+ genotype. In the +/- group, variation in the amount of visceral AT was not associated with differences in triglyceride concentration. However, hypertriglyceridemia and an increased cholesterol-to–HDL cholesterol ratio were observed in the hyperinsulinemic state irrespective of LPL-HindIII genotype status. Finally, similar positive correlations were observed between visceral AT accumulation and plasma insulin level in the homozygous (+/+) and heterozygous (+/-) groups, suggesting that the hyperinsulinemic–insulin-resistant state that is frequently associated with visceral obesity is independent of LPL-HindIII genotype. These results suggest that the HindIII polymorphism may modulate the magnitude of the dyslipidemic state associated with visceral obesity.


Key Words: lipoprotein lipase • visceral obesity • insulin • hypertriglyceridemia • candidate genes


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Abdominal obesity is an important risk factor for cardiovascular disease and has been associated with several metabolic complications, such as hypertension, dyslipidemia, insulin resistance, and non–insulin-dependent diabetes mellitus.1 2 3 4 5 6 7 8 Studies that have assessed the distribution of body fat by computed tomography (CT) have concluded that the amount of fat located in the abdominal cavity, the so-called intra-abdominal or visceral fat, is the most critical correlate of metabolic disturbances associated with abdominal obesity.9 10 11 However, severe metabolic complications are not observed in all viscerally obese subjects, thereby suggesting that genetic predisposition may be a key factor in the susceptibility of viscerally obese individuals to metabolic disorders.12 We have previously proposed that genetic variation at several loci that affect lipoprotein metabolism may alter the relation between visceral obesity and plasma lipoprotein levels.4 12 13 In this regard, we have shown that the magnitude of hypertriglyceridemia associated with visceral obesity and hyperinsulinemia is influenced by three common alleles at the apo E gene locus.14 15 We have also reported that variation at the apo B gene locus, as examined by EcoRI polymorphism, modulates the relation of visceral obesity to plasma apo B and LDL–apo B levels.16 These two examples provide evidence that the impact of visceral obesity on the plasma lipoprotein-lipid profile is partly dependent on the variation at two loci for apo B and apo E genes, both of which are involved in lipid transport as well as lipoprotein catabolism via specific cell-surface receptors.

Lipoprotein lipase (LPL) is an important enzyme for hydrolysis of triglyceride-rich lipoproteins, and its activity is positively correlated with the plasma HDL cholesterol level. An LPL gene HindIII polymorphism has been found in association with hypertriglyceridemia,17 18 19 decreased HDL cholesterol levels,20 increased apo B levels,19 coronary heart disease (CHD),19 21 and some features of the insulin resistance syndrome.22 Because these metabolic complications are also characteristic features of visceral obesity, we have investigated the possibility that the LPL-HindIII polymorphism may be involved in the relation of visceral obesity to plasma insulin and lipoprotein concentrations.


*    Methods
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 *Methods
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Subjects
A cohort of white men were recruited to participate in studies that were designed to investigate associations between obesity, regional adipose tissue (AT) distribution measured by CT, and plasma lipoprotein levels.11 Fifty-two subjects of this cohort agreed to participate in this study involving DNA analysis. They were all nonsmokers and free from metabolic disorders that required pharmacological treatment. All subjects were sedentary, and their body weight was stable at the time of investigation. The study was approved by the Ethics Committee on Human Research of Laval University.

DNA Analysis
Approximately 30 mL of peripheral venous blood was collected in tubes containing EDTA and kept frozen at -20°C until processing. DNA was extracted from leukocytes by standard methods after digestion with proteinase K and extraction with phenol/chloroform. Polymerase chain reaction (PCR) amplification was performed by using primers for the HindIII restriction site located in intron 8 of the LPL gene.18 Reactions were performed in a Perkin-Elmer Cetus thermal cycler (model TC) under the following conditions: initial denaturation at 95°C for 3 minutes; followed by 30 cycles at 95°C for 1 minute, 60°C for 30 seconds, and 72°C for 1 minute; and a final extension of 10 minutes at 72°C. The reaction volume of 50 µL contained 1.0 U Taq polymerase (Perkin-Elmer Cetus), 150 ng genomic DNA, 50 pmol of each oligonucleotide, and 3 µmol dNTP in the buffer recommended by the manufacturer. After amplification, 12 U HindIII was added to the PCR products and digested for 3 hours at 37°C. The resulting fragments were separated by size on an 8% nondenaturing polyacrylamide gel. The gels were run for 2 hours at 200 V, stained with ethidium bromide, and then photographed under UV transmitted light. The size of DNA fragments was estimated using PUC 19–digested Sau3A as molecular-weight standards. The amplified fragment had a size of 1.3 kb, and after digestion with HindIII, the + allele cut by HindIII resulted in fragments of 600 and 700 bp, whereas the - allele not cut by HindIII retained the size of 1.3 kb.

Measurements of Total Body Fat
Body density was measured by the hydrostatic weighing technique.23 Percent body fat was estimated from density by using the Siri equation.24 Fat mass was obtained by multiplying percent body fat by body weight. Pulmonary residual volume was measured with the helium-dilution method of Meneely and Kaltreider.25 Waist and hip circumferences were measured by standardized procedures recommended by the Airlie conference.26

CT
Cross-sectional abdominal subcutaneous and visceral AT areas were determined by CT with a Siemens Somatom DRH scanner as previously described.27 Briefly, the subjects were examined in the supine position with both arms stretched above the head. CT scans were performed at the abdominal level between the fourth and fifth lumbar vertebrae by using a radiograph of the skeleton as a reference to establish the position of the scan to the nearest millimeter. Total and visceral AT areas were calculated by delineating these areas with a graph pen and then computing the AT surfaces by using an attenuation range of -190 to -30 Hounsfield units.28 29 Abdominal visceral AT area was measured by drawing a line within the muscle wall surrounding the abdominal cavity.

Oral Glucose Tolerance Test
A 75-g oral glucose tolerance test (OGTT) was performed in the morning after an overnight fast. Blood samples were collected through a venous catheter from an antecubital vein at 15 minutes before and at 0, 15, 30, 45, 60, 90, 120, 150, and 180 minutes after glucose ingestion for determination of plasma glucose and insulin concentrations. Plasma glucose was measured enzymatically,30 whereas plasma insulin was measured by radioimmunoassay with polyethylene glycol separation.31 Plasma glucose and insulin areas under the curve during the OGTT were determined by the trapezoid method.

Plasma Lipoprotein Measurements
Blood samples were obtained in the morning after a 12-hour fast from an antecubital vein into Vacutainers (Becton Dickinson) containing EDTA. Cholesterol and triglyceride levels in plasma and lipoprotein fractions were measured enzymatically on an RA-1000 analyzer (Technicon Instruments Corp). VLDLs (d<1.006 g/mL) were isolated by ultracentrifugation,32 and the HDL fraction was obtained after precipitation of apo B–containing lipoproteins in the infranatant (d>1.006 g/mL) with heparin and MnCl2.33 The cholesterol content of HDL2 and HDL3 subfractions was determined after precipitation of HDL2 with dextran sulfate.34 Apo B and LDL–apo B concentrations were measured in the plasma and infranatant, (d>1.006 g/mL) respectively, by using the rocket immunoelectrophoretic method of Laurell35 as previously described.36

AT Biopsies and AT LPL Activity
A subsample of twenty-five subjects gave their informed consent for AT biopsies. Approximately 500 mg of AT was surgically removed under local anesthesia from the abdominal (lateral to the umbilicus) and femoral (anterior mid-thigh) adipose depots. AT samples were kept frozen at -80°C for later measurements of heparin-releasable activity37 as previously described.38 Another sample of AT was digested with collagenase,39 and isolated adipocytes were measured to determine mean fat cell size.40 The density of triolein was used to transform AT cell volume into fat cell weight. AT LPL activity was expressed in micromoles of free fatty acid per hour per 106 cells.

Plasma Postheparin LPL Activity
After a 12-hour fast, blood was collected from subjects 10 minutes after they had received an injection of heparin (10 IU/kg body wt IV). Assays for enzyme activity were performed with a modification of the method of Nilsson-Ehle and Ekman,41 as previously described.42 Briefly, plasma LPL activity was measured by using glycerol tri[14C]oleate as the substrate in an artificial emulsion prepared in 0.1 mol/L Tris-HCl buffer (pH 8.0) containing Triton X-100, and the delipidated human serum samples were incubated at 30°C for 20 minutes in the presence or absence of 1.0 mol/L NaCl. Free fatty acids released during incubation were selectively extracted, and an aliquot was counted for 14C radioactivity. LPL activity was calculated as the lipase activity sensitive to 1.0 mol/L NaCl from the total lipase activity (without NaCl). LPL activity is expressed as nanomoles of oleic acid released per milliliter of plasma per minute.

Statistical Analysis
Comparisons between the two genotype groups were performed with Student's t test. Associations between variables were analyzed within each group by using Pearson's correlation coefficient. Subjects were subdivided into groups of low versus high body mass index (BMI), low versus high visceral AT areas, and low versus high fasting insulin levels, with a BMI of <25 kg/m2 as the low value and a BMI of >27 kg/m2 as the high value.43 For visceral AT areas, the 100-cm2 value proposed by Després and Lamarche44 was used as the cutoff point, as it represents the lower limit value associated with significant but moderate disturbances in the CHD risk profile. The median value (71.5 pmol/L) of the fasting plasma insulin distribution in the overall group was selected as an arbitrary cutpoint to define subjects with low or high insulin levels. Subjects were also further subdivided on the basis of LPL-HindIII genotype. A 2x2 ANOVA was then performed to assess BMI, visceral AT, or insulin effects versus the effect of the LPL-HindIII genotype. Comparisons among subgroups were performed by using multiple-comparison ANOVA analyses and the Duncan post hoc test in situations where a significant group effect was observed. All statistical analyses were performed with the SAS statistical package (SAS Institute).


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
Fifty-two subjects were analyzed for the LPL-HindIII polymorphism. The relative allele frequencies were .24 and .76 for the - allele (noncarrier of the restriction site) and the + allele, respectively. Subjects were classified into two groups: (1) those who were heterozygous for the HindIII polymorphism (+/- group, n=23) and (2) those who were homozygous for the + allele (+/+ group, n=28). One subject who was homozygous for the - allele was excluded from analysis. The subjects' characteristics according to LPL genotype are presented in Table 1Down. The two genotype groups were comparable for age, BMI, fat mass, waist-to-hip ratio, visceral AT areas, fasting insulin, and glucose and insulin areas during OGTT. Results of Table 2Down show no difference in plasma lipoprotein levels between the two groups.


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  		Table 1. Anthropometric and Metabolic Characteristics of the Two Groups of Men Defined on the Basis of Lipoprotein Lipase (LPL)–HindIII Polymorphism


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  		Table 2. Plasma Lipid and Lipoprotein Levels in the Two Lipoprotein Lipase (LPL)–HindIII Genotype Groups

Associations between BMI, visceral AT area, and triglyceride concentration in the two genotype groups are shown in Fig 1Down. Whereas plasma triglyceride concentrations were positively associated with BMI, visceral AT area, and fasting insulin levels in the +/+ genotype group, no significant associations were found in men with the +/- genotype. Significant negative correlations were also observed between BMI, visceral AT area, fasting insulin, and plasma HDL2 cholesterol concentration in the +/+ genotype group (Fig 2Down). These associations were not found in the +/- group, with the exception of BMI. We then tested the hypothesis that this polymorphism could modify the relationship between visceral obesity and fasting plasma insulin level and the insulin response during the OGTT. Essentially similar associations among these variables were found in both genotypes (.60 <=r<=.75, P<.001; data not shown). No significant correlation was observed between visceral AT area and plasma LDL cholesterol, LDL–apo B, and total apo B in both genotypes (data not shown).



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  		Figure 1. Scatterplots showing correlations between body mass index (BMI), visceral adipose tissue (AT) area measured by computed tomography, fasting plasma insulin level, and fasting plasma triglyceride concentration in groups of men defined on the basis of their lipoprotein lipase (LPL)–HindIII genotype. Individuals homozygous for the + allele (allele cut by the restriction enzyme HindIII) were included in the +/+ group (n=26), whereas subjects heterozygous for the - allele (no HindIII restriction site) were included in the +/- group (n=23).



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  		Figure 2. Scatterplots showing correlations between body mass index (BMI), visceral adipose tissue (AT) area measured by computed tomography, fasting plasma insulin level, and plasma HDL2 cholesterol concentration in the two groups of men subdivided on the basis of their lipoprotein lipase (LPL)–HindIII genotype (n=20 and 25 for the +/- and +/+ genotypes, respectively).

To further examine the potential interaction between BMI, fasting insulin level, visceral AT area, and LPL HindIII genotype with plasma lipoprotein levels, subjects in both genotypes were then subdivided according to BMI (low BMI<25 kg/m2; high BMI>27 kg/m2). No significant differences were observed in plasma triglyceride levels among the four subgroups, although a trend was noted for higher triglyceride concentrations among overweight men with the +/+ genotype (Fig 3Down). When subjects were subdivided on the basis of visceral AT areas, men with elevated levels of visceral AT (area >=100 cm2) and with the +/+ genotype had higher plasma triglyceride levels compared with +/+ subjects with low levels of visceral AT (Fig 3Down). In the +/- group, variation in the amount of visceral AT was not associated with differences in triglyceride concentration. Thus, the hypertriglyceridemic effect associated with visceral obesity appeared to be restricted to the +/+ genotype. Subgroups were also formed on the basis of fasting insulin levels (low versus high) by using the median value (71.5 pmol/L) of the fasting insulin distribution of the whole sample as the cutoff point. Elevated triglyceride levels were observed in the hyperinsulinemic state, irrespective of LPL genotype.



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  		Figure 3. Bar graphs showing comparison of plasma triglyceride levels within each lipoprotein lipase (LPL)–HindIII genotype between men with low vs high body mass index (BMI), low vs high fasting insulin level, and low vs high visceral adipose tissue (AT) area. The median value of the insulin distribution in the overall group was used to define subjects with low or high insulin levels. The number within each bar identifies each subgroup, whereas the number above the SE indicates a significant difference with the corresponding group (P<=.05). Numbers of subjects in each subgroup (from left to right) were n=7, 16, 8, and 18 for BMI; n=7, 16, 9, and 17 for visceral AT area; and n=11, 12, 11, and 15 for fasting insulin level.

Similar analyses were also performed for the cholesterol-to–HDL cholesterol ratio (not shown). No significant differences were observed among the four subgroups on the basis of low or high BMI. Visceral obesity had a tendency to be associated with a higher cholesterol- to–HDL cholesterol ratio in the presence of the +/+ genotype, whereas in +/- subjects, high or low visceral AT areas could not discriminate between a high and low cholesterol-to–HDL cholesterol ratio. Finally, a higher cholesterol-to–HDL cholesterol ratio was observed in the two groups with high insulin levels, suggesting that this relation may be independent of the HindIII genotype.

Although the LPL polymorphism identified with HindIII is found in a noncoding DNA sequence (intron 8) of the gene, we tested whether it would influence AT and postheparin LPL activities (Table 3Down). No significant differences were found between the two genotypes, suggesting that the presence or absence of the HindIII restriction site does not alter plasma and AT LPL activities. When subgroups were formed on the basis of low and high BMI, visceral AT areas, and fasting insulin, no significant differences were observed between subgroups for AT and postheparin LPL activities (data not shown).


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  		Table 3. Lipoprotein Lipase (LPL) Activities in Subgroups of Men Defined on the Basis of LPL-HindIII Genotype


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Abdominal obesity combined with an increased accumulation of visceral AT is associated with alterations in indices of plasma glucose-insulin homeostasis and in the plasma lipoprotein profile.10 11 45 However, because substantial heterogeneity remains among abdominally obese subjects, we have proposed that visceral obesity represents a condition that may exacerbate the genetic susceptibility to non–insulin-dependent diabetes mellitus, dyslipoproteinemia, and CHD.4 13 In this regard, we have previously shown that genetic variation at two major genes involved in lipoprotein metabolism has divergent effects on dyslipidemia in visceral obesity. An EcoRI variant in the apo B gene appeared to be associated with elevated apo B and LDL–apo B concentrations in visceral obesity,16 whereas the apo E polymorphism seemed to influence plasma triglyceride levels in abdominally obese, hyperinsulinemic subjects,14 15 in contrast to its usual effect on LDL cholesterol in the general population.46 Because LPL activity is an important correlate of plasma triglyceride47 48 and HDL cholesterol49 levels, the main objective of this study was to verify whether the LPL-HindIII polymorphism could influence the magnitude of dyslipidemia (hypertriglyceridemia and low HDL cholesterol concentrations) generally observed in visceral obesity. Results of the present study suggest that visceral obesity may be associated with hypertriglyceridemia and low HDL cholesterol concentrations in subjects who are homozygous for the + allele of the HindIII restriction site in intron 8 of the LPL gene. The + allele of LPL-HindIII has been previously associated with hypertriglyceridemia and premature CHD17 18 19 21 and with low HDL concentrations.20 To the best of our knowledge, this is the first time that an interaction with visceral obesity, a common correlate of the high triglyceride–low HDL cholesterol dyslipidemic phenotype, has been reported.

In a sample of 370 normoglycemic Hispanic and 520 normoglycemic non-Hispanic white subjects, Ahn et al22 have recently reported that individuals with the +/+ genotype at the LPL-HindIII restriction site had higher fasting plasma insulin and triglyceride concentrations and reduced HDL concentrations compared with subjects with the +/- genotype. In the present study, the +/+ genotype was associated with hypertriglyceridemia and low HDL concentrations in the presence of visceral obesity. However, essentially similar correlations were noted between visceral AT accumulation and plasma insulin levels in the two genotype groups, suggesting that the hyperinsulinemic effect associated with visceral obesity was not altered by the HindIII polymorphism at the LPL locus. Thus, the magnitude of the hyperinsulinemic/insulin-resistant state associated with visceral obesity appears to be independent of HindIII genotype. In contrast to the study of Ahn et al,22 the present results do not support the notion that the LPL-HindIII genotype may be a marker for susceptibility to develop an insulin-resistant/hyperinsulinemic state. With regard to hypertriglyceridemia and a decreased HDL cholesterol level, the polymorphism may exacerbate the dyslipidemic state that is associated with excess visceral AT. At this time, we cannot rule out the possibility that the difference between the two studies is caused by low power level resulting from the small sample size on which the present report is based.

The +/+ HindIII genotype altered the association between BMI, insulinemia, and visceral obesity with fasting triglyceride levels because significant correlations were found only in the +/+ group. Essentially similar results were observed when plasma HDL2 cholesterol was used as the dependent variable. These effects on triglyceride and HDL2 cholesterol levels are consistent with a hypothesis of a physiological role for LPL, which not only hydrolyzes triglyceride-rich lipoproteins but also modulates plasma HDL levels. Several metabolic and experimental studies have shown that a high LPL activity is generally associated with high plasma HDL levels, especially the HDL2 subfraction.49 For these reasons, it is not surprising that triglycerides and HDL2 cholesterol were altered in a reciprocal manner, but our results emphasize that the magnitude of this effect is much greater in the homozygous +/+ genotype.

The LPL-HindIII polymorphism is located in intron 8 of the LPL gene and therefore should not be associated with differences in enzyme activity and theoretically, should not be the cause of the observed effects. Accordingly, femoral and abdominal AT LPL activities were not different between the two genotypes; postheparin plasma LPL activity was also similar in the two groups. Thus, it is likely that the LPL-HindIII polymorphism is in linkage disequilibrium with a functional mutation in the LPL gene or in another gene that could predispose individuals to dyslipidemia. In addition, the observed effect may also be due to differences in regulation of the LPL gene between the two genotypes. Insulin is an important regulator of the LPL enzyme, and this hormone may regulate LPL at the mRNA50 and/or posttranscriptional51 level. For example, the + allele could be associated with a functional LPL enzyme that is less sensitive to insulin and may result in a reduced response of LPL to insulin in visceral obesity. Other regulators could also be involved in mediating the effects described here.

In conclusion, these results indicate that the dyslipidemia associated with abdominal visceral obesity, particularly plasma triglycerides and HDL2 cholesterol, may be modulated to a significant extent by variation in the LPL gene, despite its lack of effect on measurable LPL activity. Thus, this LPL polymorphism may be considered as another genetic marker that influences plasma lipoprotein levels and presumably CHD risk in relation to the level of visceral fat. Obviously, it will be necessary to examine interactions among several candidate genes for a proper assessment of CHD risk. However, studies based on large cohorts will be needed to examine even simple interactions among apo E, apo B, and LPL genes.


*    Acknowledgments
 
This study was supported by the Medical Research Council of Canada (MRC), the Heart and Stroke Foundation of Canada, and the Canadian Diabetes Association. M.-C. Vohl and B. Lamarche received MRC fellowships during the course of this study. The authors wish to express their gratitude to the research personnel involved in collection of the data. The contribution of the staff of the Lipid Research Center, Diabetes Research Unit, and Physical Activity Sciences Laboratory is acknowledged.

Received December 10, 1994; accepted March 1, 1995.


*    References
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 *References
 

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