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Journal of Lipid Research, Vol. 45, 1885-1891, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease

Margaret E. Brousseau^2,*, Allison L. Goldkamp^*, Dorothea Collins, Serkalem Demissie, Allison C. Connolly^*, L. Adrienne Cupples, Jose M. Ordovas^**, Hanna E. Bloomfield, Sander J. Robins and Ernst J. Schaefer^*

^* Lipid Metabolism Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, and Department of Medicine, New England Medical Center, Boston, MA
Department of Veterans Affairs Cooperative Studies Program Coordinating Center, West Haven, CT
Biostatistics Department, Boston University School of Public Health, Boston, MA
^** Nutrition and Genomics Laboratory, JM-United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA
Center for Chronic Disease Outcomes Research, Veterans Affairs Medical Center, Minneapolis, MN
Department of Medicine, Boston University School of Medicine, Boston, MA

Published, JLR Papers in Press, August 1, 2004. DOI 10.1194/jlr.M400152-JLR200

¹ This paper was presented in part at the 2nd Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology, Washington, DC, May 11–13, 2001.

² To whom correspondence should be addressed. e-mail: margaret.brousseau{at}tufts.edu

	ABSTRACT

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Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; 40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of >40, who had corresponding values of 3.2% (P = 0.06), 1.5% (P < 0.01), and 18.2% (P < 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL (–32%; P < 0.01) but higher levels of small, dense LDL (+59%; P < 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 ± 0.87 vs. 20.63 ± 0.80 nm; P < 0.003).

In men with low HDL-C and CHD: 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil.

Supplementary key words fibrate • genetics • high density lipoprotein cholesterol • lipids

	INTRODUCTION

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Coronary heart disease (CHD) remains the leading cause of death in the United States (1). A number of studies have shown that plasma lipoprotein concentrations are significant predictors of CHD risk (2–5). Thus, genes with key roles in lipoprotein metabolism are excellent candidates for interindividual variation in susceptibility to CHD (6). Among these candidate genes is LPL, which hydrolyzes triglyceride-rich lipoproteins, such as chylomicrons and VLDLs, generating free fatty acids and glycerol for energy utilization and storage (7, 8). By acting as a ligand in lipoprotein-cell surface interactions, LPL also mediates the cellular uptake of lipoproteins (9).

Several common variants, or polymorphisms, have been identified in the LPL gene, as reviewed by Murthy, Julien, and Gagne (10). The majority of these are synonymous polymorphisms (11) that do not affect the protein sequence of LPL. However, three nonsynonymous variants that alter the protein sequence of LPL, namely D9N, N291S, and S447X, are among the most widely studied in terms of their relationships with plasma lipoproteins and CHD risk (12, 13). The D9N and N291S variants are associated with decreased LPL activity (14), whereas the S447X variant, which causes a deletion of the last two amino acids in the LPL protein, is associated with increased LPL activity (15).

The present study represents an extension of our earlier work with the Framingham Offspring Study (FOS) population. In FOS, the D9N and N291S alleles were associated with lower levels of high density lipoprotein cholesterol (HDL-C) and a trend toward increased triglycerides (16). In contrast, the S447X allele was associated with higher levels of HDL-C, decreased triglycerides, and reduced CHD risk in FOS males (17). To further explore the role of these LPL variants in CHD risk, we examined their associations with plasma lipid and lipoprotein levels, response to gemfibrozil therapy, and CHD end points in men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to examine the potential benefits of increasing HDL-C in men with established CHD, who had low HDL-C as their primary lipid abnormality. Additionally, we have compared the genotypic data generated in VA-HIT with that generated in men without CHD from FOS, stratified according to HDL-C level.

	METHODS

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Subjects
The rationale, design, and methods for VA-HIT have been described elsewhere in detail (18). Briefly, men were recruited at 20 Department of Veterans Affairs medical centers throughout the United States. Eligibility for the trial required a documented history of CHD, an age of <74 years, an absence of coexisting conditions, an HDL-C level of 40 mg/dl (1.0 mmol/l), an LDL-C of 140 mg/dl (3.6 mmol/l), and a plasma triglyceride concentration of 300 mg/dl (3.4 mmol/l). Information on age, alcohol consumption, smoking status, blood pressure, body mass index (BMI), and diabetes were available for all subjects enrolled in VA-HIT. However, informed consent for DNA analysis was only obtained from some of the subjects; thus, only these samples could be used in our genotyping analysis. Ninety-three percent of these subjects were white (Table 1), with no differences noted in the race distribution among subjects within each genotype. Data used in our statistical analyses were obtained at baseline, with the exception of those used to examine the relationships between genotype and the plasma lipid response to gemfibrozil (1,200 mg/day), which were obtained at month 7.

Analysis of lipoprotein subclass concentrations and particle size by NMR
The distribution of lipoprotein subclasses and particle size were determined by proton NMR spectroscopy, as previously described (25, 26). The concentrations of six VLDL (V6–V1), three LDL (L3–L1), and five HDL (H5–H1) subclasses, listed from largest to smallest with respect to particle size (nm), are provided by this methodology. VLDL levels are expressed in units of triglyceride (mg/dl), whereas LDL and HDL subclass levels are expressed in units of cholesterol (mg/dl).

DNA analysis
Genomic DNA was extracted from whole blood samples using either QIAamp mini kits (Qiagen) or Generation Capture Column kits (Gentra Systems). Genotyping of the LPL N291S and S447X variants was carried out on an Applied Biosystems 7700 sequence detection system, using TaqMan probes for allelic discrimination. A detailed description of this methodology has previously been reported (27, 28). For the N291S and S447X variants, PCR amplification was performed with the following primer pairs: 5'-AGGGCTCTGCTTGAGTTGTAGAAA-3' and 5'-CTGAGAACGAGTCTTCAGGTACATTTT-3' (N291S) and 5'-AGGAAAGGCACCTGCGGTAT-3' and 5'-CAGGATGCCCAGTCAGCTTTA-3' (S447X). For each genotype, PCR amplification was carried out in the presence of two probes, each of which had a different reporter dye attached to its 5' end (FAM^TM or VIC^TM) and a fluorescent quencher (TAMRA^TM) attached to its 3' end. One probe was complementary to the wild-type DNA strand and the other to the DNA strand with the mutation. PCR was performed in a 10 µl reaction volume, as previously described (27, 28), using two steps of 50°C for 2 min and 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. Genotyping of the D9N variant was performed manually, as previously described (29).

Statistical analyses
To evaluate the relationships between LPL genotype and plasma lipids and lipoproteins, we used analysis of covariance techniques, adjusting for the potential confounders of age, BMI, smoking status, hypertension, and diabetes. Chi-square tests were used for categorical measures, and either two-sample t-tests or Wilcoxon rank sums tests were used for continuous measures. SAS version 8 was used for all analyses. Analyses of time-to-event data were performed, and relative risks were calculated, using Cox proportional hazards models, with LPL genotype as the explanatory variable and adjustments made for the aforementioned confounders as well as treatment group.

	RESULTS

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Subject characteristics
To further investigate the frequency distribution and phenotypic effects of three common LPL variants, we analyzed 899 men in VA-HIT who had consented to DNA analysis. The demographic and biochemical characteristics of these subjects are presented in Table 1. This group of men had a mean age of 64 ± 7 years and a mean BMI of 29 ± 5 kg/m², with normal levels of TC, LDL-C, and triglycerides. Because of the selection criteria of VA-HIT, the mean level of HDL-C in these men was low (32 ± 5 mg/dl). This level resulted in a mean ratio of TC to HDL-C of 5.7, a value that is significantly higher than that defined as favorable (30).

Genotype distribution of LPL variants in VA-HIT
DNA analysis revealed that, among men in VA-HIT, 5.3% were carriers of the LPL N9 allele, 4.5% were carriers of the S291 allele, and 13.0% were carriers of the X447 allele (Table 2). Comparatively, the meta-analysis of Wittrup, Tybjaerg-Hansen, and Nordestgaard (13) identified heterozygote frequencies of 2–4% for LPL D9N, 1–7% for LPL N291S, and 17–22% for LPL S447X. Based on these data, it appears that the LPL N9 allele occurs with increased frequency in the VA-HIT population, whereas the LPL X447 allele occurs with decreased frequency.

Association of LPL variants with plasma lipid and lipoprotein subclass concentrations at baseline
We have previously reported that male carriers of either the LPL N9 or S291 alleles in FOS had significantly lower levels of plasma HDL-C (–7.1%; P = 0.03) than did noncarriers (16), whereas carriers of the LPL X447 allele had significantly higher levels of HDL-C (+5.3%; P = 0.008) and lower triglyceride levels (–14%; P = 0.01) (17). In VA-HIT, we did not observe significant associations between baseline plasma lipid levels and LPL genotype (Table 4). Although HDL-C concentrations were lower in carriers of the D9N and N291S variants relative to noncarriers, neither of these differences was statistically significant (P = 0.30 for both comparisons). As was the case in FOS, carriers of the LPL X447 allele in VA-HIT had relatively lower levels of triglycerides (153 ± 66 vs. 164 ± 69 mg/dl) and higher levels of HDL-C (32.7 ± 6.3 vs. 31.7 ± 5.1 mg/dl) than did noncarriers, but these differences were not statistically significant. Because VA-HIT consisted of a high number of men with diabetes and/or insulin resistance, we also examined our data for interactions between diabetes and insulin resistance and each LPL genotype in predicting plasma levels of HDL-C and triglycerides. Although no statistically significant (P < 0.05) interactions were observed, a few were close to statistical significance. Specifically, the P value for the interaction between LPL S447X and insulin resistance in predicting plasma HDL-C was 0.05, whereas that between LPL D9N and diabetes was 0.06.

Association of LPL variants with the plasma lipid and lipoprotein response to gemfibrozil
When on-trial concentrations of plasma lipids were compared in noncarriers versus carriers of either the LPL N9 or S291 allele, no statistically significant differences were observed (data not shown). This was likewise the case when data were expressed in terms of percentage change from baseline. In carriers of the LPL S447X variant, a relatively greater percentage reduction in plasma triglycerides versus placebo was observed in noncarriers compared with carriers (–27% vs. –20%; P < 0.04). However, this finding was most likely attributable to the higher plasma triglycerides seen in noncarriers at baseline, with on-trial concentrations of triglycerides being nearly identical in carriers (111 ± 51 mg/dl) versus noncarriers (114 ± 49 mg/dl) of the LPL S447X variant.

On-trial concentrations of plasma lipoprotein subclasses according to LPL genotype are provided in Table 5. The most striking differences in lipoprotein subclass concentrations in carriers versus noncarriers were seen among the LDL subclasses according to LPL D9N genotype. On gemfibrozil, carriers of the LPL N9 allele had significantly lower levels of large LDL (–32%) but significantly higher levels of small, dense LDL (+59%) than did noncarriers. This is in contrast to baseline values, in which differences in LDL subclass levels were not observed among the LPL D9N genotypes. The substantial differences in concentrations of large and small LDL observed in N9 carriers versus noncarriers translated into a mean LDL particle diameter of 20.14 ± 0.87 nm for carriers, which was significantly smaller than that of 20.63 ± 0.80 nm for noncarriers (P < 0.003). In contrast, no statistically significant differences were observed in on-trial concentrations of lipoprotein subclasses for the LPL N291S and S447X genotypes.

	DISCUSSION

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HDL deficiency is the most common lipid abnormality observed among patients with premature CHD (31). It has been reported that more than 50% of the variation in HDL-C levels in humans is genetically determined (32), with gene products that influence the amount and nature of lipid contained within HDL particles having important effects on the metabolism of HDL and apoA-I. Included among these gene products is LPL. We have previously reported that genetic variation at the LPL locus was associated with plasma lipoprotein levels and CHD risk in men from the FOS (16, 17). To further explore the role of common LPL variants in the modulation of CHD risk at the population level, we examined the relationships between three LPL polymorphisms, plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in men from the VA-HIT. VA-HIT is distinct from other populations used previously to examine such associations in that it consists solely of men with preexisting CHD, low HDL-C, and normal LDL-C.

In VA-HIT, 5.3% of men were carriers of the LPL N9 allele, 4.5% were carriers of the LPL S291 allele, and 13.0% were carriers of the LPL X447 allele. Comparatively, the meta-analysis of Wittrup, Tybjaerg-Hansen, and Nordestgaard (13) identified heterozygote frequencies of 2–4% for LPL D9N, 1–7% for LPL N291S, and 17–22% for LPL S447X for white subjects. To further investigate the associations between these LPL genotypes and CHD risk, we compared men in VA-HIT with men without CHD from FOS, who were stratified according to HDL-C level (40 or <40 mg/dl). The contrast between VA-HIT and FOS men with HDL-C 40 provided a comparison of those with low HDL-C and CHD with those who have neither, whereas the contrast between VA-HIT and FOS men with HDL-C < 40 provided a comparison of those who have CHD versus those without CHD among men with low HDL-C. In contrast to what was seen in VA-HIT, these analyses revealed that the frequency of the LPL N9 allele was not significantly increased in the group of men from FOS having an HDL-C of <40 mg/dl compared with men from FOS having an HDL-C of 40. However, similar to what was seen in VA-HIT, the LPL S291 and X447 alleles were significantly increased and decreased, respectively, in men from FOS with low HDL-C relative to men in FOS with normal HDL-C. Taken together with the meta-analysis of Wittrup, Tybjaerg-Hansen, and Nordestgaard (13), our data suggest that the LPL N9 allele is associated with increased CHD risk, whereas the LPL S291 and X447 alleles may be more strongly associated with HDL-C phenotype than with CHD risk. In support of this concept, a number of studies have reported increased frequency of the mutant LPL N9 allele in patients with CHD (13, 33–38).

The LPL N9, S291, and X447 alleles have been reasonably consistent in terms of their associations with plasma lipid concentrations (13). The N9 and S291 alleles are associated with lower levels of HDL-C and higher levels of triglycerides, whereas the converse is true for the X447 allele. The differential effects of these variants on plasma lipid levels may be related to their location within the LPL protein, with the D9N and N291S variants located in the N terminus and the S447X variant located in the C terminus (10). In the present study, we did not observe any statistically significant relationships between these common LPL variants and plasma lipid concentrations at baseline. The lack of significant association is likely the result of the homogenous nature of VA-HIT with respect to plasma lipid levels. Alternatively, the lack of association may be attributable to the fact that the effects of these variants on HDL-C levels is masked by other, more potent genetic factors in this population of men with low HDL-C.

A novel aspect of this study concerns our examination of the relationships between these LPL variants and the lipoprotein response to a fibric acid derivative (gemfibrozil). To our knowledge, only one other study has addressed the influence of LPL genotype on response to a lipid-lowering agent (fluvastatin) (39). Because gemfibrozil has been shown to modulate triglyceride levels, in part, via its effects on LPL gene expression (40), we believe that our study is particularly relevant. As discussed above, we did not detect significant relationships between any of the LPL genotypes and plasma lipid concentrations at baseline or on trial. However, when we examined the distribution of cholesterol among lipoprotein particles, significant associations were observed between the LPL D9N variant and on-trial concentrations of LDL subclasses. Specifically, carriers of the LPL N9 allele had significantly higher plasma concentrations of small, dense LDL during gemfibrozil therapy than did noncarriers. This is in contrast to baseline values, in which significant differences in LDL subclass levels were not observed among the genotypes. Thus, carriers of the LPL N9 allele experienced an increase in small, dense LDL in response to gemfibrozil, whereas noncarriers experienced a decrease. The differential response may relate to genotype-specific differences in LPL activity (14) and, in turn, their effects on triglyceride levels, which are known to be an important determinant of LDL composition and particle size (41). On the other hand, it is also known that LPL can bind to LDL (42), suggesting that the less common N9 allele may be associated with altered uptake of LDL during gemfibrozil therapy. Compatible with this concept, Fisher et al. (43) have recently reported that the LPL N9 allele was associated with the bridging of LDL to monocytes in vitro. It is further possible that the LPL D9N variant is in linkage disequilibrium with a polymorphism located within, or near, the peroxisome proliferator response element of the LPL promoter, whereby the N9 allele could mediate the functional responsiveness of LPL to fibrate therapy. Finally, the differences in response seen in carriers versus noncarriers may be attributable to distinct structural changes in LPL as a result of the aspartic acid-to-asparagine amino acid substitution, a concept supported by the molecular modeling work of Razzaghi et al. (44).

We also evaluated our data for associations between LPL genotype and CHD outcomes. In VA-HIT, no statistically significant relationships were observed between the LPL D9N and N291S genotypes and CHD end points, with only a trend toward increased risk for CHD end points seen in carriers of the LPL N9 (HR = 1.27) and S291 (HR = 1.21) alleles. These results are compatible with the meta-analysis of Wittrup, Tybjaerg-Hansen, and Nordestgaard (13), in which odds ratios for ischemic heart disease in carriers of the N9 and S291 alleles ranged from 0.8 to 2.4 (mean of 1.4) and from 0.9 to 1.5 (mean of 1.2), respectively, with neither value being statistically significant (P = 0.2). The LPL S447X variant was not associated with risk for CHD end points in our study. Although this finding is in contrast to studies that have shown an inverse association between the X447 allele and CHD risk (13, 17), other studies have yielded results similar to ours (33, 37–39). Included among the latter is the study of Spence, Ban, and Hegele (38), in which no association was found between the S447X variant and either carotid artery plaque at baseline or carotid artery plaque progression. Overall, the literature is not consistent with respect to associations between LPL polymorphisms and cardiovascular disease end points. As noted by Spence, Ban, and Hegele (38), these disparities are not surprising, considering the multiple roles of LPL in vivo. Thus, a particular association in one specific population may not translate to others.

In conclusion, our data show that, in men with low HDL-C and CHD, 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C levels, whereas the X447 allele is less frequent, and 2) the LPL N9 allele is associated with the LDL subclass response to fibrate therapy. These results provide new insight into the mechanisms responsible for the wide range of response to lipid-lowering therapy that is often observed at the population level.

	ACKNOWLEDGMENTS

 
This work was supported by Grant R01 HL-60935 from the National Institutes of Health, by contract 53-19550-50-003 from the United States Department of Agriculture Agricultural Research Service, and by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. The authors are grateful to Judith R. McNamara and Tatyana Massov for excellent technical assistance.

Submitted on April 21, 2004
Revised on July 21, 2004

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