Review
Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: A systematic in-depth review

https://doi.org/10.1016/j.exger.2008.11.003Get rights and content

Abstract

High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals.

HDLC levels are under considerable genetic control with heritability estimates of up to 80%. The identification and characterization of genetic variants associated with HDLC concentrations can provide new insights into the background of longevity. This review provides an extended overview on the current genetic-epidemiological evidence from association studies on genes involved in HDLC metabolism. It provides a path through the jungle of association studies which are sometimes confusing due to the varying and sometimes erroneous names of genetic variants, positions and directions of associations. Furthermore, it reviews the recent findings from genome-wide association studies which have identified new genes influencing HDLC levels.

The yet identified genes together explain only a small amount of less than 10% of the HDLC variance, which leaves an enormous room for further yet to be identified genetic variants. This might be accomplished by large population-based genome-wide meta-analyses and by deep-sequencing approaches on the identified genes. The resulting findings will probably result in a re-drawing and extension of the involved metabolic pathways of HDLC metabolism.

Introduction

High-density lipoproteins (HDL) are a heterogeneous group of particles composed of a core of cholesteryl ester and triglycerides surrounded by an amphipathic layer of free cholesterol, phospholipids and apolipoproteins (apo) (Klos and Kullo, 2007).

HDL particles exhibit multiple antiatherogenic effects (Kontush and Chapman, 2006). They shuttle cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues in need of large amounts of cholesterol (Bruce et al., 1998), an important step that relieves the peripheral cells from cholesterol burden (Fig. 1). The concept for this complex process was first proposed by Glomset et al. 40 years ago (Glomset, 1968) and is called reverse cholesterol transport. It is thought to represent the basis for the antiatherogenic properties of HDL (Kontush and Chapman, 2006, Von Eckardstein et al., 2001). Furthermore, HDL has antioxidative properties due to associated antioxidative enzymes and expresses anti-inflammatory activity in various pathways.

Fig. 1 illustrates the major routes of lipoprotein metabolism to allow a better understanding of the HDL metabolism (Kwan et al., 2007). HDL precursor particles are secreted as disc-shaped structures by the liver and intestine and can absorb free cholesterol from cell membranes, a process mediated by ABCA1, apoA-I and apoA-IV. While ABCA1 presents the best understood active cholesterol efflux mechanism, the HDL-mediated removal of free cholesterol from the peripheral cells is also aided by other active transporters such as ABCG1 as well as by passive diffusion which can be enhanced by plasma membrane receptors such as SCARB1 (Cavelier et al., 2006). ApoA-I is the major apolipoprotein of HDL and activates the enzyme lecithin:cholesteryl acyltransferase (LCAT), which esterifies the accepted free cholesterol to allow more efficient packaging of the cholesterol for transport. By acquisition of additional apolipoproteins, cholesteryl esters and triglycerides, HDL3 particles are transformed into spherical HDL2 particles (Dieplinger et al., 1985). Reverse cholesterol transport can take three different routes. First, large HDL particles with multiple copies of apoE can be taken up by the liver via the LDL receptor (Bruce et al., 1998). Second, the accumulated cholesteryl esters from HDL can be selectively taken up by the liver mediated by SR-B1 (Acton et al., 1996). This receptor is expressed primarily in liver and nonplacental steroidogenic tissues. Third, cholesteryl esters are transferred by the cholesteryl ester transfer protein (CETP) from HDL to triglyceride-rich lipoproteins (Bruce et al., 1998). Serum HDL cholesterol levels are influenced by the complexity of these reverse cholesterol transport processes. Disturbances in the concentrations of apoproteins, function of enzymes, transport proteins, receptors, other lipoproteins and their clearance from plasma can have a major impact on the antiatherogenic properties in HDL.

High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects (Kontush and Chapman, 2006) and HDL cholesterol (HDLC) concentrations show a strong inverse correlation with the risk of coronary artery disease (CAD) (Lewington et al., 2007). Epidemiological studies highlighted the antiatherogenic function of HDLC and showed that an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for CAD in men and women, respectively (Wilson, 1990, Linsel-Nitschke and Tall, 2005). A recent meta-analysis (Lewington et al., 2007) including prospective observational studies with HDLC measurements available in 150,000 individuals demonstrated a strong negative association with ischemic heart disease mortality in every age group, with no evidence of a threshold beyond which higher HDL cholesterol was no longer associated with lower mortality. On average, 13 mg/dL higher HDL cholesterol was associated with about a third lower ischemic heart disease mortality. Within every age group, the strength of this association was comparable for men and women. Moreover, clinical trials have established that increasing HDLC levels by drugs could reduce CAD risk (Gotto, 2001, Manninen et al., 1988, Rubins et al., 1999, Kronenberg, 2004), thus bringing longer life expectancy. This hypothesis is compatible with observations that familial hyperalphalipoproteinemia often coexists with longevity (Patsch et al., 1981), and that higher HDLC levels are found among healthy elderly aged 85–89 years as compared to those in middle-aged subjects (Nikkila and Heikkinen, 1990). Accordingly, HDL and molecules involved in HDL metabolism seem to be attractive candidates for longevity-promoting factors (Arai and Hirose, 2004).

Since HDLC levels are under considerable genetic control with heritability estimates of up to 80% (Kronenberg et al., 2002, Perusse et al., 1997, Wang and Paigen, 2005, Goode et al., 2007), the identification and characterization of genetic variants associated with HDLC concentrations can provide useful information related to genotype–phenotype relationships and give new insights in the background of longevity.

This article reviews the current genetic-epidemiological evidence from association studies on genes involved in HDL metabolism. Genetic association studies establish estimates for a difference of mean HDLC levels among subjects with a certain genetic variant compared to the others and thus a measure of association between the genetic background and HDLC outcome in human beings. This overview should provide a path through the jungle of association studies often reporting different names and positions for the same genetic variant under study. Furthermore, the associations are sometimes reported in the direction of the “risk allele”, that is the genetic variant associated with increased CAD risk and thus lower HDLC levels, or in the direction of the “minor allele”, that is the less frequently appearing variant in the population, which may even differ between study populations. Furthermore, it reviews the recent findings from genome-wide association studies, which have identified new genes influencing HDLC levels and provides a first taste on the future. It is not intended to provide an overview on functional studies.

Section snippets

Methods on the literature search

The literature search for genes previously reported for association with HDLC was performed in PubMed using search terms such as “(meta-analysis OR associat* OR epidemiolog*) AND (polymorphism OR genetic OR mutation) AND HDL AND human” with an Entrez Date in PubMed until April 2008 (EDAT: the date the citation was added to PubMed). Results were complemented by knowledge of the lipid-experienced investigators of this study.

Eligible studies for data extraction were meta-analyses, population-based

Cholesteryl ester transfer protein (CETP)

The CETP gene is located on chromosome 16 and consists of 16 exons and 15 introns and is a member of the lipopolysaccharide binding protein gene family (Yamashita et al., 2001). The gene locus is highly polymorphic with several common polymorphisms as well as rare mutations (Thompson et al., 2007).

CETP is a key plasma protein that influences circulating levels of HDLC by mediating the transfer of esterified cholesterol from HDL to apoB-containing particles in exchanges for triglycerides (Tall,

Results on rarely investigated genes

Table 11 provides the results on genes rarely investigated which showed a significant association with HDLC levels in at least one large study (n > 1000). It might be a worthwhile attempt to replicate the shown associations with HDLC in further large studies.

Negative results on often investigated genes

Many studies investigated the association of the APOA4 gene and HDLC levels. The most frequently investigated polymorphisms are the T347S (rs675) and Q360H (rs5110). Especially the large studies with sample sizes above 1000 did not show a significant association of these polymorphisms with HDLC levels (data not shown).

The same holds true for APOB: several studies investigated the association of this gene with HDLC levels. Large studies, however, showed non-significant results (data not shown).

Common vs. rare variants

Common variants are those that appear in the general population with a frequency >1% or even >5% of subjects. These variants often show, individually, rather small associations. Kathiresan et al. illustrated, however, that a combining of the information on several of these low-impact common variants can contribute to some extent to the prediction of HDLC levels (Kathiresan et al., 2008a). They studied nine SNPs at nine loci in 5287 subjects, created a genotype score on the basis of the number

Advantages of genome-wide association studies

The recent introduction of microarray technology for genotyping allows the genotyping of several hundreds of thousands genetic variants in a single person in one step. This enables genome-wide association (GWA) studies by genotyping a large number of individuals with phenotypes of interest at reasonable costs. Compared to a hypothesis-driven candidate gene approach as described in the chapters above the hypothesis-free GWA studies can identify new susceptibility genes without making any a priori

Heterogeneity of low-HDL syndromes

HDL cholesterol levels have a strong genetic determination, with heritability estimates ranging in most cases between 40% and 60% (Wang and Paigen, 2005, Goode et al., 2007, Kronenberg et al., 2002). As it is the case with many intermediate cardiovascular risk phenotypes, low HDLC can be either monogenic or purely environmental or, in most cases is multifactorial/polygenic in origin (Von Eckardstein, 2006). The most common inherited form of low HDLC is familial hypoalphalipoproteinemia, which

Relationship between HDLC and triglyceride genes

Many genes control lipolysis of plasma triglycerides, a process that also affects HDLC levels through the delivery of apolipoproteins and phospholipids to HDL (Holleboom et al., 2008). There are several genes influencing both HDLC and triglyceride levels which have been identified by candidate gene and hypothesis-free GWA study approaches. For example associations between common SNPs at the APOA5 locus and triglyceride concentrations as well as HDLC levels are significant and relatively

HDLC genes and atherosclerosis

The epidemiological evidence for an inverse association of HDLC concentrations with the risk of coronary artery disease is very strong (Lewington et al., 2007), but the causality of this relationship is hard to prove. Since HDL levels are strongly determined by genetic variants (besides environmental factors), a causal association between HDLC and CAD can be demonstrated by showing an association of these genetic variants with risk of CAD. The idea behind is the concept of Mendelian

Conclusions

Several decades of research on the genetic contribution to HDL metabolism have identified a large number of genes contributing to the antiatherogenic HDLC concentrations. The variants detected in these genes together explain only a small amount of less than 10% of the HDLC variance, but the heritability of HDLC is estimated to be up to 80%. This provides an enormous room for further yet to be identified genetic variants. This might be accomplished by genome-wide association studies. Since the

Acknowledgments

Our own research discussed in this review was funded by grants from the “Genomics of Lipid-associated Disorders – GOLD” of the “Austrian Genome Research Programme GEN-AU”, the Austrian National Bank (Project 12531) and the Austrian Heart Fund to F. Kronenberg and by the German National Genome Research Net, the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, Germany and the NIH-subcontract from the Children’s Hospital, Boston, USA, under the prime Grant 1 R01 DK075787-01A1,

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