Total Lipids In Small Hdl

Background

Lipids, such as cholesterol and triglycerides, are essential for cellular function but are insoluble in water. They are transported throughout the bloodstream within lipoprotein particles, which are complexes of lipids and proteins. High-Density Lipoprotein (HDL) is one such class of lipoprotein, often referred to as “good cholesterol” due to its role in reverse cholesterol transport, where it helps remove excess cholesterol from peripheral tissues and transport it back to the liver for excretion or recycling. HDL exists in various sizes and densities, with small HDL particles representing a distinct subfraction. “Total lipids in small HDL” refers to the collective amount of cholesterol, triglycerides, and phospholipids contained within these smaller, denser HDL particles. This specific measurement offers a more granular view of HDL function and metabolism compared to total HDL cholesterol.

Biological Basis

Small HDL particles play a crucial role in lipid metabolism, particularly in the initial stages of reverse cholesterol transport. They are often rich in APOA-I, which is essential for activating lecithin-cholesterol acyltransferase (LCAT), an enzyme that esterifies free cholesterol, allowing it to be sequestered within the HDL core and promoting HDL maturation. Small HDL can also arise from the remodeling of larger HDL particles by enzymes like hepatic lipase and cholesteryl ester transfer protein (CETP). The dynamic interplay of various apolipoproteins, such asAPOA-I, APOB, APOC-III, and APOE, as well as specific genes, influences the synthesis, remodeling, and catabolism of these particles. ^[1] For example, variants in genes like GCKR (e.g., the P446L allele, rs1260326 ) have been associated with altered concentrations of APOC-III, an inhibitor of triglyceride catabolism, which can indirectly impact lipid partitioning within lipoproteins.^[1]

Clinical Relevance

The concentration of total lipids in small HDL particles is recognized as a clinically relevant marker, particularly in the context of cardiovascular disease risk. While total HDL cholesterol levels are a common metric, specific subfractions, including small HDL, may offer more precise insights into an individual’s risk profile. Lower levels of small, dense HDL particles are often associated with an increased risk of atherosclerosis and cardiovascular events, even when total HDL cholesterol levels appear within a normal range. This is because small HDL particles are generally considered more effective in their anti-atherogenic functions, such as cholesterol efflux. Studies have explored various lipid phenotypes, includingHDL2 and HDL3cholesterol subfractions obtained through chemical precipitation, and lipoprotein particle concentrations measured by nuclear magnetic resonance, to better understand their roles in polygenic dyslipidemia.^[1] Genetic factors are known to contribute to dyslipidemia, a condition characterized by abnormal lipid levels. ^[1] For instance, the LPA coding SNP rs3798220 has been associated with LDLcholesterol and lipoprotein(a) levels.^[1]

Social Importance

Cardiovascular diseases, often linked to dyslipidemia, represent a major global health burden. Understanding specific lipid markers like total lipids in small HDL is crucial for improving risk stratification and developing targeted interventions. The ongoing research into the genetic basis of lipid metabolism, including the role of common variants in influencing lipoprotein profiles^[1]contributes significantly to personalized medicine. By identifying individuals with genetic predispositions to adverse small HDL profiles, public health initiatives and healthcare providers can implement earlier preventive strategies, lifestyle modifications, or pharmacological treatments. This knowledge empowers individuals to take proactive steps towards managing their cardiovascular health, ultimately reducing disease prevalence and improving overall population well-being.

Limitations

Study Design and Phenotype Characterization

The investigations primarily involved large-scale genome-wide association studies (GWAS) and meta-analyses, pooling data from thousands of individuals across multiple cohorts. ^[1] Despite these considerable sample sizes, the common genetic variants identified collectively explain only a modest fraction of the observed variation in lipid concentrations within the population. ^[2] This suggests that current studies may still lack sufficient power to detect all contributing variants, especially those with smaller effects or those that are rare, leading to a substantial portion of heritability remaining unexplained.

Furthermore, inconsistencies in phenotype measurement and participant ascertainment across the contributing studies introduce potential limitations. While most cohorts mandated fasting blood samples for lipid measurements, the duration of fasting varied ^[1] which could influence lipid profiles. The handling of individuals on lipid-lowering therapy was also inconsistent; some studies excluded these participants, while others lacked such information or were conducted before these therapies were common, thus not accounting for their effects. ^[1] Critically, these studies predominantly focused on broad lipid traits such as “HDL cholesterol” ^[1]rather than the more specific “total lipids in small hdl.” The genetic architecture influencing distinct HDL subclasses may vary, meaning that direct inference regarding the genetic basis of “total lipids in small hdl” from these broader HDL cholesterol findings is limited and warrants further specialized investigation.

Generalizability Across Populations

A significant limitation is the predominant focus of these studies on populations of European ancestry. ^[1] Many cohorts explicitly selected individuals of European descent, with non-European individuals often excluded from analysis. ^[2] While some efforts were made to extend findings to a multiethnic cohort encompassing Chinese, Malays, and Asian Indians ^[1]this was an attempt to replicate rather than an integral part of the initial discovery phase across diverse populations. The genetic underpinnings of lipid metabolism, including “total lipids in small hdl,” can differ significantly across various ancestral groups due to variations in allele frequencies, linkage disequilibrium patterns, and environmental exposures. Consequently, the direct applicability and transferability of these findings to non-European populations may be restricted, highlighting a need for more inclusive genetic studies.

Unexplained Heritability and Remaining Knowledge Gaps

Despite the identification of numerous genetic loci, a substantial portion of the heritability for lipid traits remains unexplained by common variants. ^[2]This “missing heritability” suggests that other genetic factors, such as rare variants, structural variations, or complex gene-gene and gene-environment interactions, may play significant roles that were not fully captured or modeled in these analyses. Although adjustments for basic demographic factors like age and sex were implemented, the intricate interplay between genetic predispositions and broader environmental or lifestyle factors (e.g., diet, physical activity, smoking) on “total lipids in small hdl” has not been comprehensively elucidated. For instance, some loci exhibit significantly different effects between males and females^[2]indicating complex sex-specific interactions that require deeper exploration. Furthermore, while associations were established for several genes, the precise biological mechanisms by which many of these variants impact lipid metabolism and, specifically, the composition of “total lipids in small hdl,” often require further functional characterization.

Variants

Genetic variations play a crucial role in determining an individual’s lipid profile, including the levels of total lipids within small high-density lipoprotein (HDL) particles. Several single nucleotide polymorphisms (SNPs) and their associated genes have been identified as key contributors to dyslipidemia and related cardiovascular risks. These variants often influence the synthesis, metabolism, or transport of various lipid components.

The FADS1 and FADS2 genes, located closely together, encode fatty acid desaturase enzymes that are essential for synthesizing polyunsaturated fatty acids (PUFAs) from dietary precursors. The variant rs174564 in this region is associated with altered lipid profiles. Specifically, variations in FADS1-FADS2 have shown strong associations with various fatty acids present in serum phospholipids. ^[3] These desaturases impact the composition of cell membranes and the availability of lipid signaling molecules, which can indirectly affect the packaging and transfer of lipids into HDL particles. Similarly, the CELSR2 gene, often discussed alongside PSRC1 and SORT1, is linked to lipid metabolism, particularly low-density lipoprotein (LDL) cholesterol levels. TheCELSR2 variant rs12740374 has been shown to be strongly associated with reduced LDL cholesterol concentrations. ^[4] While primarily known for its LDL association, changes in LDL metabolism can have compensatory effects on HDL particles and their lipid content.

Other significant genes include CETP and LIPC, which are central to HDL metabolism. The gene CETP(Cholesteryl Ester Transfer Protein) plays a critical role in transferring cholesteryl esters from HDL to other lipoproteins, primarily LDL and very-low-density lipoprotein (VLDL), in exchange for triglycerides.^[4] The HERPUD1 - CETP variant rs12446515 likely influences CETP activity, thereby affecting HDL cholesterol and its lipid composition; lower CETP activity typically leads to higher HDL cholesterol levels and potentially different small HDL lipid profiles. LIPCencodes hepatic lipase, an enzyme that hydrolyzes phospholipids and triglycerides in HDL and chylomicrons. TheLIPC variant rs11632618 is associated with changes in HDL cholesterol concentrations, as reduced hepatic lipase activity generally leads to increased HDL cholesterol and larger, less dense HDL particles. ^[1] The APOB - TDRD15 variant rs562338 is relevant due to APOB’s central role as the primary structural protein of LDL and VLDL, dictating their assembly and metabolism. Variations in APOBare strongly associated with LDL cholesterol and triglyceride levels^[1] which can secondarily influence the lipid exchange and overall lipid balance affecting small HDL.

Further genetic variations involve genes with diverse cellular functions that indirectly impact lipid metabolism. ALDH1A2 (Aldehyde Dehydrogenase 1 Family Member A2) is involved in retinoic acid synthesis, a pathway that can influence gene expression related to lipid metabolism. While specific variants like rs1601933 , rs4775033 , and rs1318175 may have subtle effects, their influence on metabolic pathways could modulate the total lipid content in small HDL particles. ^[5] The BCAM (Basal Cell Adhesion Molecule) variant rs118147862 , and variants in TOMM40 (rs111784051 ) and PCIF1 (rs6065908 ), are also implicated in lipid metabolism, though their precise mechanisms on small HDL lipids are still being explored. TOMM40 is involved in mitochondrial protein import, a fundamental process for cellular energy and lipid homeostasis. ^[5] PCIF1(PCNA-interacting Factor 1) is a less directly studied gene in lipid metabolism, but its role in gene regulation or cellular processes could contribute to the variability observed in total lipids in small HDL.

Key Variants

RS ID	Gene	Related Traits
rs139953093 rs6073958	PLTP - PCIF1	free cholesterol:totallipids ratio, intermediate density lipoprotein measurement cholesteryl esters:totallipids ratio, high density lipoprotein cholesterol measurement phospholipids:total lipids ratio phospholipids in small HDL measurement free cholesterol in small HDL measurement
rs1260326	GCKR	urate measurement total blood protein measurement serum albumin amount coronary artery calcification lipid measurement
rs525028	APOC3 - APOA1	high density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, lipid measurement total cholesterol measurement, low density lipoprotein cholesterol measurement cholesteryl ester measurement, low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, phospholipid amount
rs10889335 rs1007205	DOCK7	level of phosphatidylinositol serum metabolite level total lipids in small hdl measurement cholesterol in small HDL measurement phospholipids in small HDL measurement
rs4939883	LIPG - SMUG1P1	lipid measurement high density lipoprotein cholesterol measurement total cholesterol measurement depressive symptom measurement, non-high density lipoprotein cholesterol measurement level of apolipoprotein A-I in blood serum
rs77960347	LIPG	apolipoprotein A 1 measurement level of phosphatidylinositol total cholesterol measurement high density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement
rs112875651 rs28601761	TRIB1AL	low density lipoprotein cholesterol measurement total cholesterol measurement reticulocyte count diastolic blood pressure systolic blood pressure
rs80189144	BAZ1B - BCL7B	appendicular lean mass cholesteryl esters:total lipids ratio, blood VLDL cholesterol amount leucine measurement saturated fatty acids measurement cholesterol:totallipids ratio, high density lipoprotein cholesterol measurement
rs34060476	MLXIPL	testosterone measurement alcohol consumption quality coffee consumption measurement free cholesterol measurement, high density lipoprotein cholesterol measurement triglycerides:totallipids ratio, high density lipoprotein cholesterol measurement
rs4240624 rs983309	PPP1R3B-DT	C-reactive protein measurement alkaline phosphatase measurement calcium measurement depressive symptom measurement, non-high density lipoprotein cholesterol measurement schizophrenia

Classification, Definition, and Terminology

Operational Definition of Lipid Phenotypes

The precise definition of lipid phenotypes, such as HDL cholesterol, in the context of genetic association studies like those examining polygenic dyslipidemia, often relies on an operational framework. ^[1]For the purpose of these studies, the phenotype was defined as “sex-specific residual lipoprotein concentrations”.^[1] This conceptual approach transforms raw lipid measurements by regressing out the effects of age, age squared, and ancestry-informative principal components to create a standardized residual with a mean of 0 and a standard deviation of 1. ^[1] This operational definition allows researchers to isolate the underlying genetic contributions to lipid levels by accounting for major environmental and demographic confounders. ^[1]

Standardized Measurement and Adjustment Criteria

The measurement of lipid concentrations, including HDL cholesterol, followed specific research criteria to ensure consistency and minimize variability. Participants in the stage 2 studies had “fasting lipid concentrations” available, which is a critical criterion for accurate lipid assessment. ^[1] Furthermore, individuals known to be undergoing “lipid-lowering therapy” were systematically excluded from the analysis, except for the ISIS study where such therapies were not common during the examination period. ^[1]Beyond these participant selection criteria, lipoprotein concentrations underwent further adjustments for confounding variables; specifically, measurements were adjusted for the effects of sex, age, and age squared across multiple studies, and for ten ancestry-informative principal components in the FHS study.^[1] These rigorous adjustments are crucial for defining the specific research criteria applied to lipid phenotypes, including HDL cholesterol, during the genotype-phenotype association analysis. ^[1]

Key Terminology in Dyslipidemia Research

Within the context of polygenic dyslipidemia research, several key terms are central to understanding lipid profiles and their genetic underpinnings. “Lipoprotein concentrations” refer to the measured levels of various lipid-carrying particles in the blood, which include “HDL cholesterol”, “LDL cholesterol”, and “triglycerides”. ^[1] HDL cholesterolspecifically denotes the cholesterol content within high-density lipoprotein particles, a crucial measure in cardiovascular health assessments. “Lipid-lowering therapy” refers to pharmacological interventions designed to reduce circulating lipid levels, and its consideration is vital for accurate research measurements.^[1] Additionally, “ancestry-informative principal components” are statistical constructs used to account for population substructure, a critical factor in genome-wide association studies to prevent spurious associations. ^[1] These terms constitute the standardized vocabulary for describing and analyzing lipid traits in genetic studies aimed at identifying variants contributing to dyslipidemia. ^[1]

Causes of Total Lipids in Small HDL

The Polygenic Basis of Lipid Dysregulation

The total lipid content within small high-density lipoprotein (HDL) particles is influenced by a complex interplay of genetic factors, primarily through a polygenic architecture. This means that numerous common genetic variants, each contributing a small effect, collectively determine an individual’s overall lipid profile and susceptibility to dyslipidemia. Research indicates that common variants at many loci contribute to dyslipidemia, suggesting a broad genetic basis rather than a single causative gene.^[1]These inherited variations contribute to the fundamental biological processes governing lipid synthesis, transport, and catabolism, ultimately shaping the quantity and composition of lipids within various lipoprotein subfractions, including small HDL.

Genetic Variants Affecting Apolipoprotein Metabolism

Variations within genes encoding key apolipoproteins significantly impact the total lipids found in small HDL. Apolipoproteins like APOA-I, APOB, APOC-III, and APOEare integral components of lipoprotein particles, dictating their structure, metabolism, and interactions with enzymes and receptors in lipid pathways.^[1]Genetic differences in these apolipoprotein genes can alter the efficiency of lipid transfer, cholesterol efflux, and triglyceride metabolism, thereby influencing the remodeling of HDL particles. Consequently, these genetic influences on apolipoprotein levels and function directly affect the lipid cargo and overall size of HDL, contributing to variations in total lipids within the smaller HDL subfractions.

Impact of Metabolic Pathway Genes

Specific genetic loci that regulate crucial metabolic pathways can also profoundly affect the total lipids in small HDL. For instance, theGCKR P446L allele (rs1260326 ) is significantly associated with increased concentrations of APOC-III. ^[1] APOC-IIIacts as an inhibitor of triglyceride catabolism, meaning its elevated levels, driven by theGCKRvariant, can lead to higher circulating triglyceride concentrations. This increased triglyceride burden impacts the exchange of lipids between triglyceride-rich lipoproteins and HDL particles, leading to triglyceride enrichment of HDL and its subsequent remodeling into smaller, denser particles with altered total lipid content.

Biological Background

HDL Structure and Function

High-density lipoprotein (HDL) particles are essential for reverse cholesterol transport, a critical process that removes excess cholesterol from peripheral cells and returns it to the liver for excretion. The specific composition of these particles, including their total lipid content, is vital for their functional capacity, particularly within the smaller HDL subclasses. Apolipoprotein AI (APOA1) serves as the principal structural protein of HDL, and its presence, alongside phospholipids, is fundamental to the formation and maturation of HDL particles, including precursor forms like prebeta-HDL, which are key initial acceptors of cellular cholesterol. Studies have indicated that increased levels of prebeta-HDL, APOA1, and phospholipid can be observed in models expressing human phospholipid transfer protein (PLTP) and human APOA1 transgenes, highlighting the interconnectedness of these components in overall HDL dynamics. ^[6]

Genetic Regulation of Lipid Metabolism

Genetic factors significantly influence lipid metabolism and the resulting plasma lipoprotein profiles. Hepatocyte Nuclear Factor 4 Alpha (HNF4A) is a critical transcription factor responsible for regulating the expression of genes involved in glucose and lipid homeostasis. Variants withinHNF4A have been associated with altered beta-cell function and type 2 diabetes, conditions frequently linked to dyslipidemia. Similarly, Hepatocyte Nuclear Factor 1 Alpha (HNF1A) plays a role in orchestrating gene expression, particularly within the liver, and specific variants, such as HNF1A G319S, have been connected to variations in plasma lipoproteins. These transcription factors establish complex regulatory networks that govern the synthesis, catabolism, and overall concentrations of circulating lipids, including the specific total lipids found within small HDL particles. ^[7]

Key Enzymes and Regulatory Molecules in HDL Dynamics

The dynamic remodeling of HDL particles and their specific lipid content is precisely controlled by a range of key enzymes and regulatory molecules. Phospholipid transfer protein (PLTP) is an enzyme that facilitates the transfer of phospholipids between various lipoproteins and contributes to the conversion of larger HDL particles into smaller ones. This enzymatic activity directly impacts the pool of small HDL and its total lipid composition. Furthermore, Endothelin-1, a powerful vasoconstrictor, has been shown to have an association with high-density lipoprotein cholesterol levels, suggesting a potential interplay between vascular regulation and systemic lipid metabolism. Such interactions can carry significant implications for the development of conditions like coronary artery disease.^[8]

Systemic Implications and Pathophysiological Links

The intricate balance of total lipids in small HDL particles is an integral part of broader systemic lipid homeostasis, and disruptions in this balance contribute to various pathophysiological processes. Dyslipidemia, characterized by abnormal levels of lipids in the blood, is often a polygenic condition, with multiple common genetic variants acting in concert to influence plasma high-density lipoprotein cholesterol levels and other lipid traits. These genetic predispositions, which impact elements like transcription factors and lipid-modifying enzymes, can lead to chronic homeostatic disruptions within the body. Such imbalances in lipoprotein metabolism, including alterations in small HDL, are recognized as significant risk factors for the development of metabolic disorders like type 2 diabetes and cardiovascular diseases, including coronary artery disease.^[1]

Pathways and Mechanisms

Core Lipid Synthesis, Catabolism, and Remodeling

The fundamental processes governing the total lipids found within lipoproteins like small HDL involve intricate metabolic pathways for synthesis, breakdown, and redistribution of lipids. Cholesterol biosynthesis is a tightly regulated process, with key enzymes such as HMG-CoA reductase, encoded by HMGCR, catalyzing early steps. ^[9] Similarly, mevalonate kinase, encoded by MVK, participates in cholesterol synthesis, while MMAB is involved in cholesterol degradation, indicating a balanced system of lipid production and clearance. ^[4]

Lipid catabolism, particularly of triglycerides, is critical for modulating the lipid content of HDL particles. Lipoprotein lipase (LPL) and hepatic lipase, encoded by LIPC and LIPG, are central to the hydrolysis of triglycerides within lipoproteins. ^[10] Factors like ANGPTL3 and ANGPTL4serve as major regulators by inhibiting lipoprotein lipase, thereby influencing circulating triglyceride and HDL levels.^[4] Moreover, apolipoprotein C3 (APOC3) is known to inhibit LPL activity and decrease the fractional catabolic rate of very low-density lipoproteins (VLDL), contributing to hypertriglyceridemia. ^[1]The transfer of lipids between lipoprotein classes is also crucial, with phospholipid transfer protein (PLTP) influencing HDL cholesterol levels, and cholesteryl ester transfer protein (CETP) mediating exchanges that redistribute lipids among lipoproteins. ^[1]

Transcriptional and Post-Translational Regulation of Lipid Pathways

The expression and activity of proteins involved in lipid metabolism are meticulously controlled through various regulatory mechanisms, including gene transcription and post-translational modifications. Transcription factors like SREBP2 regulate the expression of genes such as MVK and MMAB, thereby controlling cholesterol synthesis and degradation pathways. ^[4] Another significant regulator is MLXIPL, which binds to and activates specific promoter motifs of genes involved in triglyceride synthesis, directly influencing lipid production.^[4] Gene regulation also manifests through variants influencing transcript levels, such as the rs7679 allele at the PLTP locus, which is associated with higher PLTP transcript levels and consequently higher HDL cholesterol. ^[1] Similarly, variants in the LIPC promoter can lead to altered hepatic lipase activity and HDL cholesterol concentrations. ^[1]

Post-translational modifications play a vital role in modulating protein function within lipid pathways. For instance, GALNT2, which encodes a widely expressed glycosyltransferase, may modify lipoproteins or their receptors, potentially altering their stability, recognition, or activity. ^[4]Furthermore, the alternative splicing of genes, as observed with common single nucleotide polymorphisms (SNPs) inHMGCR affecting the splicing of exon 13, can impact the final protein product and its function, affecting cholesterol metabolism. ^[9] The proprotein convertase subtilisin/kexin type 9 (PCSK9) provides another layer of regulation by promoting the degradation of the LDLR, thereby influencing LDL cholesterol clearance and indirectly impacting overall lipid flux.

Signaling Networks and Inter-Pathway Crosstalk in Lipoprotein Metabolism

Lipid homeostasis is maintained through complex signaling pathways and extensive crosstalk between different metabolic networks. Receptor activation is a key aspect, exemplified by the ABCA1 transporter, which facilitates cholesterol efflux from cells, a crucial initial step in HDL formation. ^[10] The LDLR pathway, which mediates the uptake of LDL particles by cells, is another central signaling axis in cholesterol management. ^[10] The coordinated function of these receptors ensures proper lipid transport and cellular cholesterol balance, which in turn impacts the composition of HDL.

Systems-level integration is evident in the interplay between various apolipoproteins and their associated genes, particularly the cluster involving APOA5, APOA4, APOC3, and APOA1. APOA1 is the primary structural protein of HDL, essential for its integrity and function, while APOC3profoundly impacts triglyceride catabolism, demonstrating direct pathway crosstalk within lipoprotein metabolism.^[1] Transcription factors like HNF4A and HNF1A are also integrated into this network, as their mutations can lead to altered plasma cholesterol levels, indicating their hierarchical regulatory influence on lipid pathways. ^[1] This intricate web of interactions ensures robust control over the total lipids circulating in the bloodstream, including those in small HDL particles.

Genetic Determinants and Dyslipidemia Mechanisms

Genetic variations are significant determinants of circulating lipid levels, and their dysregulation underlies many forms of dyslipidemia. Genome-wide association studies (GWAS) have identified numerous loci that influence concentrations of HDL, LDL, and triglycerides, including genes like ABCA1, APOB, CETP, GALNT2, GCKR, HMGCR, LDLR, LIPC, LPL, MLXIPL, PCSK9, and the APOA5-APOA4-APOC3-APOA1 cluster. ^[10] These genetic insights reveal specific mechanisms through which lipid pathways can be perturbed, contributing to adverse lipid profiles.

Pathway dysregulation can have profound effects on cardiovascular health. For example, a null mutation in humanAPOC3 has been shown to result in a favorable plasma lipid profile, characterized by lower triglycerides and potentially offering cardioprotection. ^[11] This highlights APOC3 as a critical therapeutic target for managing dyslipidemia. Compensatory mechanisms may also exist within the complex polygenic architecture of lipid metabolism, where multiple genetic variants interact to modify lipid levels. ^[1]Understanding these genetic determinants not only explains individual variations in lipid profiles but also identifies potential therapeutic targets for interventions aimed at modifying total lipids in small HDL and other lipoprotein fractions to reduce cardiovascular disease risk.

References

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[2] Aulchenko YS, et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.” Nat Genet, vol. 40, no. 2, 2008, pp. 198–206.

[3] Sabatti C, et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.” Nat Genet, vol. 40, no. 2, 2009, pp. 198–206.

[4] Willer CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-69.

[5] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.” PLoS Genet, vol. 4, no. 11, 2008, e1000282.

[6] Jiang X, et al. “Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.”

[7] Hansen T, et al. “Hepatocyte nuclear factor-4alpha (HNF4A): gene associations with type 2 diabetes or altered beta-cell function among Danes.” J. Clin. Endocrinol. Metab., vol. 90, no. 5, 2005, pp. 3054–3059.

[8] Pare G, et al. “Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol.”Am. J. Hum. Genet., vol. 80, no. 4, 2007, pp. 673–682.

[9] Burkhardt R, et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, vol. 28, no. 10, 2008, pp. 1821-27.

[10] Aulchenko YS, et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 41, no. 1, 2009, pp. 111-15.

[11] Pollin TI, et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 326, no. 5951, 2009, pp. 440-42.