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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3858-3863
Copyright © 2004 by The Endocrine Society

The –514 C->T Hepatic Lipase Promoter Region Polymorphism and Plasma Lipids: A Meta-Analysis

Aaron Isaacs, Fakhredin A. Sayed-Tabatabaei, Omer T. Njajou, Jacqueline C. M. Witteman and Cornelia M. van Duijn

Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. C. M. van Duijn, Department of Epidemiology and Biostatistics, Erasmus Medical Center, Postbus 1738, 3000 DR Rotterdam, The Netherlands. E-mail: c.vanduijn{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Investigations of the –514 C->T single nucleotide polymorphism (SNP) in the hepatic lipase (HL) gene promoter region (LIPC) have yielded contradictory results regarding its association with changes in plasma lipids. The current study is a meta-analysis of 25 publications on this SNP, comprising over 24,000 individuals, and its relationship with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, and HL activity. Significant decreases were observed in HL activity for both the CT and TT genotypes compared with the CC genotype [weighted mean difference (WMD), –5.83 mmol/liter·h (95% confidence interval, –8.48, –3.17) and –11.05 mmol/liter·h (95% confidence interval, –14.74, –7.36), respectively]. Moreover, significant increases in HDL were found; the CT to CC comparison showed an increase in WMD of 0.04 mmol/liter (95% confidence interval, 0.02, 0.05) mmol/liter, and the increase in the TT vs. CC difference was WMD of 0.09 mmol/liter (95% confidence interval, 0.07, 0.12). These changes appear to be stepwise, implying an allele dosage effect. All P values for these associations were less than 0.001. This meta-analysis demonstrates the importance of the –514C->T SNP in determining HL activity and plasma HDL concentration and helps quantify the role that hepatic lipase plays in the metabolism of HDL.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
HEPATIC LIPASE (HL), a glycoprotein member of the lipase superfamily, plays an important role in the metabolism and modeling of both pro- and antiatherogenic lipoproteins. Synthesized and secreted by the liver, HL carries out several metabolic functions, including the hydrolysis of triglycerides, the lypolysis of phospholipids, the modeling of small, dense atherogenic low density lipoprotein cholesterol (LDL) particles, and the catabolism of high density lipoprotein cholesterol (HDL) (1).

Numerous polymorphisms in the HL gene, located at 15q21 and spanning nine exons, are under investigation. Four common single nucleotide polymorphisms (SNPs) are located in the promoter region (an A->G at –763 bp, a T->C at –710 bp, a C->T –514 bp upstream of the promoter, and a G->A SNP at –250 bp); these have been reported to be in complete linkage disequilibrium (2, 3). One in particular, designated alternately as the –480 C->T or the –514 C->T SNP (4, 5), has received considerable attention. This polymorphism, located in the promoter region, has been demonstrated to influence HL activity levels (6, 7, 8, 9, 10, 11, 12, 13). HL activity is substantially decreased in carriers of the T allele. In addition, in some populations the –514 SNP (as the polymorphism will be designated in this article) demonstrated a significant positive effect on plasma HDL levels (11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24). This finding, however, has been attenuated by other studies that fail to demonstrate an association (7, 8, 12, 25, 26, 27, 28, 29, 30). With respect to other plasma lipids, one study documents a marginally significant association between the SNP and increased total cholesterol (TC) in male control subjects (29).

The use of widely varying, sometimes heterogeneous, populations as well as the small sample sizes used in many of these studies may explain these discrepancies, especially considering the comparatively small measurable association of the mutation, with respect to plasma lipids. In an effort to resolve these differences and gain some indication of the overall clinical significance of this polymorphism, the current study examines the literature available through January 2004 in a meta-analysis, a method that may help to alleviate the inconsistencies traditionally associated with genetic association studies (31).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
PubMed, the online bibliographic resource, provided the means for identifying association studies pertaining to the –514 C->T polymorphism and HL activity and plasma lipids. These articles, supplemented by others extracted from their references and by additional information obtained via contact with the authors, totaled 47. Studies presenting either HL activities, plasma lipid levels, or both were considered for inclusion. Twelve studies were excluded due to the fact that relevant data (such as plasma lipid concentrations or number sampled for each genotype) were not presented (32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43). Nine others failed to distinguish between the CT and TT genotypes and did not enter into the meta-analysis for this reason (16, 25, 44, 45, 46, 47, 48, 49, 50). Another study appeared to present a subset of data published in a separate article (51).

Altogether, 25 studies contributed to this meta-analysis. Sample sizes varied widely, ranging from 21–9117. Three studies used a case-control design in which the cases were comprised of coronary artery disease (CAD) patients (9, 11, 29), one used hemodialysis patients as cases (52), and five included only high risk individuals (8, 9, 13, 17, 52). One study by Shohet et al. (9) described a case-control study and also presented data for a group of CAD patients. Two reports examined the effect of the –514C->T polymorphism on patients receiving lipid-lowering therapy (12, 13); only baseline data entered into this analysis. One article documented cross-sectional analysis of a large cohort (53). The remaining publications studied either random samples from the general population or relatively healthy individuals. Included are several cohort-based analyses; in these instances, however, the design was that of a nested case-control study.

Ten of the studies included only male subjects (6, 8, 9, 10, 11, 12, 13, 17, 28, 30); similarly, two analyzed only females (20, 54). The remainder sampled both genders; several studies reported significant differences between men and women. Because of this, both overall and gender-stratified analyses were performed to determine whether this gender difference might affect results.

Measurements of plasma lipids took place via colorimetric enzymatic reaction in articles included in the meta-analysis. The HDL fractions in most instances were determined by measurement of the cholesterol levels in the supernatant after precipitation of apolipoprotein B-containing particles. LDL levels were usually estimated via Friedewald’s equation.

Genotype and allele proportions in these samples did not, for the most part, differ from Hardy-Weinberg equilibrium (HWE). One population that failed to meet HWE reported on a high risk population (11), in which deviations from Hardy-Weinberg proportions are expected if the gene is associated with the risk of disease. Another study by Fang et al. (26) was in accordance with HWE overall and in men, but not women.

Statistical analysis

Entry of the available data into Cochrane’s Review Manager (RevMan version 4.2, the Cochrane Collaboration, Oxford, UK) allowed for extensive analysis. Before pooling the studies, tests for homogeneity were performed. Sensitivity analysis was conducted by reviewing the included studies a second time to detect sources of heterogeneity and, consequently, to perform additional analysis with and without those studies. In those cases where SEs were originally reported, SDs were calculated. All data in this analysis are presented as the mean ± SD. The method of moments technique, proposed by DerSimonian and Laird (55), provided a way to calculate weighted mean differences (WMD) in a random effects model for pooled data.

Published findings showing differences on the basis of gender necessitated stratified analysis by sex. Differences in allele frequency between ethnic groups further necessitated a breakdown by ethnicity (Caucasian, African-American, and Asian). Finally, stratification by population (high or low risk) was performed to determine whether risk factor profiles played a role in this association. Risk categories were determined on the basis of the presence (or absence) of disease (such as CAD or diabetes) or other risk factors (such as children of CAD patients).

Finally, utilization of funnel plots allowed us to ascertain the possible influence of publication bias. These plots were conducted with RevMan software.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Twenty-five studies included in this analysis comprised 24,252 subjects, although this total fluctuates according to the data available for a given outcome. Six articles (791 subjects) provided the data analyzed for HL activity; 23 included data analyzed for plasma HDL levels (23,792 individuals). Anderson et al. (53) (n = 9,117) and Couture et al. (14) (n = 2,667) used the largest samples, both in Caucasian populations. The majority of the studies sampled middle-aged subjects, although several used younger groups, and others consisted largely of more elderly people.

Overall, the frequency of the T allele was 25.3%. This estimate varied widely in the studies, ranging from just over 55% in an Oji-Cree (indigenous Canadian) ethnic population (27) to 17% in one of the Caucasian samples (15). Table 1Go details the number of subjects and genotype distributions of the included studies.


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  		TABLE 1. Characteristics of included studies

 
HL activity decreased significantly for both the CT and the TT genotypes compared with the CC genotype [WMD, –5.83 mmol/liter·h [95% confidence interval (CI), –8.48, –3.17; P < 0.001] and –11.05 mmol/liter·h (95% CI, –14.74, –7.36; P < 0.001), respectively]. Figure 1Go shows the negative WMDs in HL activity for carriers of the TT and CC genotypes. The difference in HL activity between the TT and CT carriers also reached statistical significance (–3.98 mmol/liter·h; 95% confidence interval –5.90, –2.05; P < 0.001).



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  		FIG. 1. Hepatic lipase activity for TT vs. CC genotypes. T, Turkish population; M, male; F, female.

 
Plasma HDL levels also differed significantly among genotypes, although previous findings were inconsistent. Mean plasma HDL levels in the CT group were increased, on the average, to 0.04 mmol/liter (95% CI, 0.02, 0.05; P < 0.001), whereas mean plasma HDL levels for TT carriers increased 0.09 mmol/liter (95% CI, 0.07, 0.12; P < 0.001) compared with the CC group, as depicted in Fig. 2Go. A significant difference also existed between the CT and TT subjects (0.06 mmol/liter; 95% CI, 0.04, 0.08; P < 0.001).



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  		FIG. 2. HDL concentrations for TT vs. CC genotypes. I, Inuit population; H, Hutterite population; O, Oji-Cree population; M, male; F, female; B, black; W, white; CAD, CAD group; Con, control group; Cas, designated cases.

 
A significant difference also existed between the CC and TT genotypes for TC (0.09 mmol/liter; 95% CI, 0.02, 0.17; P = 0.02). Analysis of the other plasma lipids, including LDL and triglycerides, failed to reveal any significant differences (Table 2Go).


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  		TABLE 2. Plasma lipids and HL activity by genotype

 
Stratification by gender, ethnicity (Caucasian, African-American, or Asian) and risk category (high or low) did not appreciably alter these associations (data not shown). The lone exception appeared to be a small, but significant, difference between WMDs in TC concentration when stratifying by ethnicity. Examining the CC and CT genotypes, the WMD of TC concentrations was significantly lower in Asians (WMD, –0.09 mmol/liter; 95% CI, –0.19, 0.01) compared with that of Caucasians (WMD, 0.06 mmol/liter; 95% CI, 0.00, 0.12).

Regarding HDL levels, stratification by ethnicity revealed that the direction of the association was consistent across ethnic groups, although the point estimates differed slightly. Funnel plots, performed to assess the possibility of publication bias, were quite symmetrical in all of the studied associations. Figure 3Go shows this plot for the studies analyzed for HDL.



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  		FIG. 3. Funnel plot of studies analyzed for HDL.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This meta-analysis used data from more than 24,000 individuals, available from 25 published studies, to reevaluate the association between the –514C->T promoter region SNP in the HL gene and plasma lipids and HL activity. The stepwise decrease in the point estimates for HL (and stepwise increase in HDL levels) suggests that an allele dosage effect occurs in this association.

In several studies the genotype frequencies did not conform to Hardy-Weinberg equilibrium proportions. In one of these, the population came from a high risk category, in which deviations from HWE are expected. In several others, however, the sample came from general population groups. The reasons behind this are unclear, although genotyping errors remain a possibility. These studies introduced significant heterogeneity to the HDL comparisons. Their exclusion eliminated the heterogeneity, but did not appreciably alter the point estimates or CIs.

Any measurement errors in the laboratory analysis of plasma lipids would be equally distributed among the three genotypes, and because weighted mean differences were calculated, this is unlikely to introduce an error in these results. The study by Grundy et al. (12) contained the smallest sample size (representing <0.09% of the total). It also featured the third smallest SD, according it a relatively large weight in the meta-analysis. The articles by Tahvanainen et al. (8) and Zambon (13) presented the smallest SDs, which, likewise, imparted high weights. Excluding these studies did not noticeably change the results, excluding the possibility of an overweighting effect on the results obtained here.

The analysis of HL activity revealed evidence of significant heterogeneity. Although this heterogeneity might lead to an overestimation of the total estimate, sensitivity analysis demonstrated that heterogeneity did not alter the significant association between the genotype and HL activity, because all of the included studies showed significant negative association between the presence of the T allele and HL activity. The Caucasian sample in the study by Vega et al. (6) included only one individual with the TT genotype; therefore, estimation of a WMD for HL activity was not possible.

An important potential source of bias in a meta-analysis is publication bias, because the likelihood of publishing a study is frequently related to the results it contains. The articles analyzed in this meta-analysis, however, include many that reported negative findings. Funnel plots, used to determine the presence of publication bias, were highly symmetrical, suggesting that this form of bias is not an issue.

A previous study noted substantially reduced transcription of HL in murine hepatocyte cells (AML12) (3). The significant decrease in HL activity for both the CT and TT genotypes (with respect to the CC group) support the association between the presence of the T allele and decreased HL transcription and, in turn, activity. Likewise, the significant increase observed in HDL levels when comparing CT and TT groups to CC support the association between this SNP and HDL levels, presumably as a result of decreased HL activity.

This analysis demonstrates the effect of the –514 C->T polymorphism on both HL activity and plasma HDL levels. The crucial question to ask concerns the effect of this SNP on cardiovascular morbidity and mortality. To date, few studies have addressed this issue. Based on the findings of the present study, we predict that TT carriers face a reduced risk of CAD, perhaps as a consequence of increased HDL levels or due to previously noted associations with increased LDL buoyancy (13, 50). Surprisingly, some studies suggest an increased risk, which requires further research.

Briefly, this meta-analysis of 25 articles shows a positive association between the –514 C->T polymorphism and HDL levels and a negative association between genotype and HL activity. These associations are largely unaffected by gender, ethnicity, and risk category.


   Footnotes
 
Abbreviations: CAD, Coronary artery disease; HDL, high-density lipoprotein cholesterol; HL, hepatic lipase; HWE, Hardy-Weinberg equilibrium; LDL, low-density lipoprotein cholesterol; SNP, single nucleotide polymorphism; TC, total cholesterol; WMD, weighted mean difference.

Received February 4, 2004.

Accepted May 14, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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