Free Cholesterol In Large Hdl
Introduction
Section titled “Introduction”Background
Section titled “Background”High-density lipoprotein (HDL) is a complex group of plasma lipoproteins that plays a pivotal role in lipid metabolism, primarily through its involvement in reverse cholesterol transport (RCT). Often referred to as “good cholesterol,” HDL facilitates the removal of excess cholesterol from peripheral cells and tissues, transporting it back to the liver for excretion or recycling. HDL particles are heterogeneous, varying in size, density, and protein and lipid composition. “Large HDL” represents a mature and cholesterol-rich subfraction of these particles, considered to be particularly effective in cholesterol efflux. “Free cholesterol” refers to unesterified cholesterol, which is a critical component of cell membranes and the initial form of cholesterol picked up by nascent HDL particles. The concentration of free cholesterol within large HDL particles reflects a specific aspect of cholesterol trafficking and HDL particle maturation.
Biological Basis
Section titled “Biological Basis”The formation and maturation of large HDL particles, and their free cholesterol content, are governed by a sophisticated network of proteins and enzymes. Cholesterol efflux from cells, primarily mediated by the ATP-binding cassette transporter A1 (ABCA1), forms nascent, lipid-poor HDL particles. These nascent particles acquire free cholesterol, which is then esterified by the enzyme lecithin-cholesterol acyltransferase (LCAT). This esterification process converts free cholesterol into cholesterol esters, which are more hydrophobic and move into the core of the HDL particle, causing it to swell and mature into larger, spherical HDL particles. These large HDL particles, rich in cholesterol esters (derived from free cholesterol), are central to the efficient delivery of cholesterol back to the liver, a process known as reverse cholesterol transport. Other key proteins like cholesteryl ester transfer protein (CETP) can exchange cholesterol esters from HDL for triglycerides in other lipoproteins, influencing HDL size and composition. Lipases such as lipoprotein lipase (LPL), hepatic lipase (LIPC), and endothelial lipase (LIPG) also remodel HDL particles, affecting their cholesterol content and size.
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of HDL cholesterol are generally associated with a reduced risk of cardiovascular disease (CVD). However, recent research suggests that the protective effect of HDL may depend not just on its quantity but also on its quality and functional capacity, including the specific content of free cholesterol within its subfractions like large HDL. Alterations in the free cholesterol content of large HDL, or in the overall metabolism of these particles, can impact their ability to effectively perform reverse cholesterol transport. Genetic variations in genes involved in HDL metabolism, such as those encodingABCA1, CETP, LPL, LIPC, LIPG, and GALNT2, have been consistently linked to variations in HDL cholesterol levels and are associated with polygenic dyslipidemia and coronary artery disease risk. . This distinction is crucial, as the biological mechanisms and clinical implications of total HDL may differ significantly from those of specific HDL subfractions or their cholesterol components, thereby limiting the direct applicability of these findings to the precise phenotype of interest. Furthermore, while the research involved a meta-analysis of multiple cohorts, comprising 8,816 participants for the initial meta-analysis of HDL cholesterol, the specific demographic and ancestral backgrounds of these individuals are not detailed within the provided context.[1] This lack of explicit information on population structure and diversity hinders the ability to confidently generalize these genetic associations across diverse ethnic groups, as genetic architecture and allele frequencies can vary substantially between populations.
Scope of Genetic Discovery and Statistical Constraints
Section titled “Scope of Genetic Discovery and Statistical Constraints”The initial genome-wide association analysis identified several loci influencing lipid concentrations based on an arbitrary significance threshold of P < 5 × 10−7. [1]While this threshold is commonly employed for initial discovery phases in large-scale genetic studies, such findings typically require rigorous replication in independent cohorts to confirm their validity and provide more precise estimates of effect sizes, which can sometimes be inflated in initial discovery scans. For instance, the reported effect size of a 2.42 mg/dl increase in HDL cholesterol per A allele forrs3764261 near CETP is derived from this initial stage and may be subject to refinement with subsequent validation studies. [1]Although the study indicates that population stratification and unmodeled relatedness had a negligible impact on the association results, the overall statistical power for detecting smaller genetic effects or those with complex interactions might still be constrained by the sample size of the initial meta-analysis.
Unexplored Biological and Environmental Influences
Section titled “Unexplored Biological and Environmental Influences”The research primarily focused on identifying novel genetic loci associated with lipid traits, leaving several critical areas unexplored regarding the comprehensive regulation of free cholesterol in large HDL. The study did not delve into the complex interplay between the identified genetic variants and various environmental factors, such as dietary habits, lifestyle choices, or co-existing medical conditions, all of which are known to profoundly influence lipid metabolism. Consequently, the extent to which gene-environment interactions might modify the observed genetic effects or contribute to the overall variability in lipid levels remains unquantified. Moreover, while the identified loci contribute significantly to our understanding of genetic influences on lipid concentrations, the study does not address the concept of “missing heritability” or fully elucidate the complete spectrum of genetic and non-genetic factors that account for the total heritable variation in these complex phenotypes.
Variants
Section titled “Variants”The composition and metabolism of high-density lipoprotein (HDL), particularly its free cholesterol content in large particles, are influenced by a complex interplay of genetic factors. Variations within several genes, including those involved in lipid transport, hydrolysis, and fatty acid synthesis, play a significant role in determining an individual’s lipid profile and cardiovascular risk. These genetic predispositions can alter enzyme activity, protein function, or regulatory pathways, leading to measurable differences in circulating lipid levels.
The Cholesteryl Ester Transfer Protein (CETP) is a crucial enzyme that mediates the exchange of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins, and triglycerides in the reverse direction. Genetic variants inCETP, such as rs72786786 and rs183130 , can influence this exchange, thereby modulating HDL cholesterol levels and the distribution of free cholesterol within large HDL particles. For instance, the A allele ofrs3764261 in CETP is associated with a 2.42 mg/dl increase in HDL cholesterol, reflecting altered CETP activity that impacts HDL composition. [1] Another significant signal, rs289714 , also demonstrates a strong association with HDL cholesterol levels. [2]
Hepatic Lipase (LIPC) is an enzyme primarily responsible for the hydrolysis of triglycerides and phospholipids in HDL, affecting the size and lipid content of HDL particles, including their free cholesterol. Variants likers1077835 , which is also associated with ALDH1A2, can modify LIPCactivity, influencing how HDL is remodeled and its capacity to manage free cholesterol efflux. Specifically,rs10468017 near LIPC is linked to an increase in HDL cholesterol concentrations by 1.76 mg/dl per T allele, underscoring its role in maintaining healthy HDL profiles. [1]Similarly, Lipoprotein Lipase (LPL) hydrolyzes triglycerides in circulating lipoproteins, indirectly affecting HDL levels and free cholesterol by processing triglyceride-rich particles. Variations such asrs15285 , rs325 , and rs144503444 in LPL can alter the enzyme’s function, with rs12678919 associated with a 2.44 mg/dl increase in HDL cholesterol and rs6993414 strongly linked to triglyceride levels.[1] The common LPL nonsense mutation S447X (rs328 ) is also recognized for its impact on lipid metabolism. [2]
Apolipoprotein E (APOE) is a key lipid-binding protein involved in the metabolism of triglycerides and cholesterol, playing a central role in the transport of lipids in the blood and brain. The variant rs429358 in APOE, a well-known polymorphism, significantly influences the binding of APOEto lipoprotein receptors, thereby affecting the uptake of cholesterol-rich particles by the liver and other tissues, and consequently impacting circulating levels of LDL and HDL cholesterol. TheAPOE-APOC1-APOC4-APOC2 gene cluster is strongly associated with LDL cholesterol, and variants like rs4420638 show a significant association with increased LDL cholesterol levels, which can indirectly affect the balance of free cholesterol in large HDL.[1] Another variant, rs1985096 , represents an additional signal for LDL association within this cluster. [2] Aldehyde Dehydrogenase 1 Family Member A2 (ALDH1A2) is involved in the synthesis of retinoic acid, a signaling molecule that can influence gene expression related to lipid metabolism. Variants such as rs261291 , rs1601935 , and rs1077835 (also associated with LIPC) may alter ALDH1A2activity, potentially affecting pathways that regulate cholesterol synthesis or efflux, and thus the levels of free cholesterol within HDL particles.
The Fatty Acid Desaturase (FADS) gene cluster, encompassing FADS1 and FADS2, encodes enzymes vital for synthesizing polyunsaturated fatty acids, which are integral components of phospholipids and cholesteryl esters within lipoproteins, including HDL. Variants such as rs174574 and rs174564 can modify desaturase efficiency, thereby influencing the lipid composition of HDL particles and their capacity to transport free cholesterol. TheFADS1-FADS2 locus has been significantly associated with metabolic traits, including LDL, indicating its broad influence on lipid profiles. [3] Phospholipid Transfer Protein (PLTP) is essential for the transfer of phospholipids and free cholesterol among various lipoprotein classes, a key process in HDL remodeling and the reverse cholesterol transport pathway. Genetic variations likers6065904 and rs6073958 in PLTPcan alter its activity, affecting HDL particle size, lipid content, and the efficiency of free cholesterol efflux.[4] Though the direct involvement of Zinc Finger Protein, Recombinant 1 (ZPR1) in lipid metabolism is less understood, its variant rs964184 is significantly associated with triglyceride concentrations, and therefore may indirectly influence HDL composition.[1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs261291 rs1601935 | ALDH1A2 | high density lipoprotein cholesterol measurement triglyceride measurement depressive symptom measurement, non-high density lipoprotein cholesterol measurement anxiety measurement, non-high density lipoprotein cholesterol measurement total cholesterol measurement |
| rs72786786 rs183130 | HERPUD1 - CETP | depressive symptom measurement, non-high density lipoprotein cholesterol measurement HDL cholesterol change measurement, physical activity total cholesterol measurement, high density lipoprotein cholesterol measurement free cholesterol measurement, high density lipoprotein cholesterol measurement phospholipid amount, high density lipoprotein cholesterol measurement |
| rs1077835 | ALDH1A2, LIPC | triglyceride measurement high density lipoprotein cholesterol measurement level of phosphatidylcholine level of phosphatidylethanolamine total cholesterol measurement |
| rs6065904 | PLTP | lipid measurement pathological gambling ADGRE5/SEMA7A protein level ratio in blood blood protein amount gut microbiome measurement |
| rs15285 rs325 rs144503444 | LPL | blood pressure trait, triglyceride measurement waist-hip ratio coronary artery disease level of phosphatidylcholine sphingomyelin measurement |
| rs964184 | ZPR1 | very long-chain saturated fatty acid measurement coronary artery calcification vitamin K measurement total cholesterol measurement triglyceride measurement |
| rs174574 | FADS2 | low density lipoprotein cholesterol measurement, C-reactive protein measurement level of phosphatidylcholine heel bone mineral density serum metabolite level phosphatidylcholine 34:2 measurement |
| rs6073958 | PLTP - PCIF1 | triglyceride measurement HDL particle size high density lipoprotein cholesterol measurement alcohol consumption quality, high density lipoprotein cholesterol measurement triglyceride measurement, alcohol drinking |
| rs174564 | FADS2, FADS1 | triglyceride measurement level of phosphatidylcholine serum metabolite level cholesteryl ester 18:3 measurement lysophosphatidylcholine measurement |
| rs429358 | APOE | cerebral amyloid deposition measurement Lewy body dementia, Lewy body dementia measurement high density lipoprotein cholesterol measurement platelet count neuroimaging measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Defining High-Density Lipoprotein Cholesterol
Section titled “Defining High-Density Lipoprotein Cholesterol”High-density lipoprotein (HDL) cholesterol is a crucial lipid trait and biomarker recognized for its significant role in cardiovascular health. Conceptually, HDL cholesterol is understood as a component of lipoproteins, which are complex particles that transport lipids, including cholesterol, through the bloodstream.[1]While the provided studies focus on overall HDL cholesterol levels, this general understanding forms the basis for defining more specific components or subtypes, such as free cholesterol within large HDL particles. Terminology often includes “HDL cholesterol” or simply “HDL,” and related concepts like the “Total/HDL cholesterol” ratio are used in clinical and research settings to assess lipid profiles.[5]
Measurement and Operationalization of HDL Cholesterol
Section titled “Measurement and Operationalization of HDL Cholesterol”The precise measurement of HDL cholesterol is fundamental for its operational definition in both clinical diagnostics and research studies. Blood samples are typically drawn after overnight fasting to ensure accurate lipid concentration determination. [2] Standard enzymatic methods are employed to quantify serum HDL concentrations, with measurements often performed using automated clinical chemistry analyzers. [3] In research, such as genome-wide association studies, HDL cholesterol concentrations are frequently adjusted for confounding factors like sex, age, and age squared, and residual values are standardized to facilitate genotype-phenotype association analyses. [2] Individuals who have not fasted before blood collection or who are diabetic are typically excluded from analyses of lipid traits like HDL cholesterol to maintain data integrity. [3]
Clinical Significance and Classification of HDL Cholesterol
Section titled “Clinical Significance and Classification of HDL Cholesterol”HDL cholesterol is critically classified as a key risk factor in the context of cardiovascular disease (CVD). High concentrations of HDL cholesterol are consistently associated with a decreased risk of coronary artery disease (CAD), with estimates suggesting that each 1% increase in HDL cholesterol concentrations may reduce CAD risk by approximately 2%.[1]Conversely, low levels of HDL cholesterol are considered a significant risk factor for coronary heart disease.[6] Genetic studies have identified specific loci, such as those near MMAB-MVK and GALNT2, that are associated with HDL cholesterol levels, highlighting the polygenic nature of dyslipidemia and the heritability of this trait. [2] Understanding these genetic influences and the clinical thresholds for “low” or “high” HDL cholesterol is vital for risk stratification and guiding lipid-lowering therapies. [1]
Biological Background
Section titled “Biological Background”High-Density Lipoproteins and Cholesterol Homeostasis
Section titled “High-Density Lipoproteins and Cholesterol Homeostasis”High-density lipoproteins (HDL) play a crucial role in maintaining cholesterol balance within the body, often referred to as reverse cholesterol transport, where excess cholesterol from peripheral tissues is transported back to the liver for excretion or recycling. High concentrations of HDL cholesterol are consistently associated with a decreased risk of coronary artery disease (CAD), with each 1% increase in HDL cholesterol concentrations estimated to reduce CAD risk by approximately 2%.[1] This beneficial effect is partly attributed to the composition and function of HDL particles, which include key components like apolipoprotein A-I (APOA1) and various enzymes.
The functionality of HDL, including its ability to handle free cholesterol, is influenced by several critical biomolecules. For instance, phospholipid transfer protein (PLTP) and lecithin-cholesterol acyltransferase (LCAT) are enzymes central to HDL remodeling and cholesterol esterification. Studies have shown that increased expression of human PLTP and APOA1 transgenes in mice leads to elevated levels of prebeta-HDL, APOA1, and phospholipids, indicating their role in shaping HDL particle characteristics. [7] LCAThas a well-established role in lipid metabolism, converting free cholesterol into cholesterol esters within HDL, and common variants in its gene can influence HDL concentrations.[1]Apolipoprotein C-III (APOC3), secreted by the liver and intestines, is another component of HDL, and it appears to enhance HDL catabolism. [8]
Genetic Determinants of Lipid Metabolism
Section titled “Genetic Determinants of Lipid Metabolism”The levels of circulating lipids, including HDL cholesterol, are highly heritable, with numerous genes and their protein products involved in their complex metabolism. [9]Genetic variations, such as single nucleotide polymorphisms (SNPs) and rare mutations, can significantly influence individual lipid profiles. For example, a null mutation in humanAPOC3 has been shown to confer a favorable plasma lipid profile and apparent cardioprotection. [8] Similarly, a common variant (rs2967605 ) in the ANGPTL4 (angiopoietin-like 4) gene is strongly associated with HDL cholesterol levels [2] highlighting specific genetic influences on HDL.
Other genes, including HNF4A (hepatocyte nuclear factor-4 alpha) and HNF1A (hepatocyte nuclear factor-1 alpha), have been linked to altered plasma cholesterol levels, with a specific HNF1AG319S variant associated with plasma lipoprotein variation[10]. [2] Large-scale genetic analyses have also identified gene clusters, such as APOA5-APOA4-APOC3-APOA1 and APOE-APOC1-APOC4-APOC2, as critical regions influencing lipid concentrations. [9] Beyond these, genes like HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), ABCA1, CETP, LDLR, LPL, and PCSK9 are also known to contribute to the genetic architecture of lipid levels. [9]
Molecular and Cellular Pathways Regulating Lipoprotein Dynamics
Section titled “Molecular and Cellular Pathways Regulating Lipoprotein Dynamics”Lipid metabolism involves intricate molecular and cellular pathways that control the synthesis, transport, and catabolism of lipoproteins. APOC3, secreted primarily by the liver and to a lesser extent by the intestines, plays a dual role by impairing the catabolism and hepatic uptake of apoB-containing lipoproteins while also appearing to enhance the catabolism of HDL particles. [8] The protein ANGPTL4provides another example of a molecular regulator, acting as an inhibitor of lipoprotein lipase (LPL), an enzyme crucial for the hydrolysis of triglycerides from circulating lipoproteins. [2]
Genetic variations can also impact post-transcriptional regulation, as seen with HMGCR, a key enzyme in cholesterol synthesis. Common SNPs in HMGCR can affect the alternative splicing of exon 13, leading to different mRNA variants. [11] The ratio of the Δexon13 HMGCR mRNA variant to total HMGCR mRNA has been observed to differ significantly based on genotype, suggesting a regulatory mechanism that influences the expression of HMGCR and, consequently, cholesterol synthesis. [11] Furthermore, transcription factors like TCF1 and MAFB are implicated in lipid regulation, with MAFB known to interact with LDL-related protein, indicating complex regulatory networks at the cellular level. [2]
Pathophysiological Implications of Dyslipidemia
Section titled “Pathophysiological Implications of Dyslipidemia”Disruptions in lipid homeostasis, commonly referred to as dyslipidemia, are major contributors to the development of cardiovascular diseases (CVDs). Atherosclerosis, the underlying pathology of many CVDs, involves the cumulative deposition of LDL cholesterol in arterial walls, ultimately leading to impaired blood flow and events like myocardial infarction or stroke.[1]Consistent evidence demonstrates a strong association between lipoprotein-associated lipid concentrations and the incidence of CVD worldwide.[1]
While high LDL cholesterol concentrations are linked to an increased risk of CAD, high HDL cholesterol concentrations are independently associated with a decreased risk. [1]This highlights the protective role of HDL in mitigating the pathophysiological processes of atherosclerosis. The complex genetic architecture of lipid levels contributes to the polygenic nature of dyslipidemia, where variations in multiple genes collectively influence an individual’s risk[9]. [2] Conditions such as type 2 diabetes are also associated with altered plasma cholesterol levels, further illustrating the systemic consequences of disrupted lipid metabolism. [12]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”HDL Biogenesis and Remodeling Pathways
Section titled “HDL Biogenesis and Remodeling Pathways”The formation and maturation of high-density lipoprotein (HDL) particles involve a complex interplay of lipid transporters and enzymes. Initial HDL biogenesis is facilitated by theABCA1transporter, which mediates the efflux of free cholesterol and phospholipids to lipid-poor apolipoprotein A-I (APOA1), forming nascent HDL particles. [9] Once formed, nascent HDL undergoes remodeling, primarily driven by lecithin-cholesterol acyltransferase (LCAT), which esterifies free cholesterol within the particle, causing it to move to the core and allowing the HDL to mature into larger, spherical particles.[2] This dynamic process is crucial for reverse cholesterol transport, where cholesterol is removed from peripheral tissues and returned to the liver.
Further remodeling and catabolism of HDL are influenced by several key proteins. Apolipoprotein C-III (APOC3), a component of HDL, appears to enhance HDL catabolism, while also impairing the catabolism and hepatic uptake of apoB-containing lipoproteins. [8] Hepatic lipase (LIPC) acts as a key enzyme in long-chain metabolism, breaking down triglycerides into diacyl- and monoacylglycerols and fatty acids, which can significantly impact the lipid composition and size of HDL particles.[13]
Transcriptional and Post-Translational Regulatory Mechanisms
Section titled “Transcriptional and Post-Translational Regulatory Mechanisms”Lipid metabolism, including the regulation of free cholesterol in large HDL, is tightly controlled at both transcriptional and post-translational levels. Key transcription factors such as hepatocyte nuclear factor 4 alpha (HNF4A) and hepatocyte nuclear factor 1 alpha (HNF1A) are essential for maintaining hepatic gene expression and overall lipid and bile acid homeostasis. [2] Although their direct influence on human HDL cholesterol is still being elucidated, their roles in liver function underscore their systemic importance in lipid regulation. Another important transcriptional regulator is MLXIPL, which binds to and activates specific motifs in the promoters of genes involved in triglyceride synthesis, thereby influencing the availability of lipids for lipoprotein assembly.[1]
Post-translational modifications and protein degradation pathways also play a critical role in modulating lipid levels. For instance, common single nucleotide polymorphisms (SNPs) inHMGCR, the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase, affect the alternative splicing of exon 13, which can alter the enzyme’s activity in cholesterol biosynthesis. [11] Furthermore, proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly impacts cholesterol levels by accelerating the degradation of the low-density lipoprotein receptor (LDLR) in a post-endoplasmic reticulum compartment. [2]
Metabolic Flux and Systemic Lipid Homeostasis
Section titled “Metabolic Flux and Systemic Lipid Homeostasis”The balance of lipid synthesis, breakdown, and transport pathways is crucial for systemic lipid homeostasis. The mevalonate pathway, a central route for cholesterol biosynthesis, involves enzymes like mevalonate kinase (MVK), which catalyzes an early step in the process .
Genetic Modifiers and Dyslipidemia
Section titled “Genetic Modifiers and Dyslipidemia”The regulation of free cholesterol in large HDL is a polygenic trait, influenced by common genetic variants across numerous loci that collectively contribute to dyslipidemia. Genome-wide association studies (GWAS) have identified multiple genes, includingABCA1, APOA cluster (A1/A4/A5/C3), CETP, LCAT, LIPC, LPL, HNF4A, HNF1A, ANGPTL4, MLXIPL, MVK, MMAB, and PCSK9, that influence circulating lipid levels. [9]These genetic variations can lead to pathway dysregulation, contributing to conditions such as coronary artery disease and other forms of dyslipidemia.[9]
The integration of these genetic findings with biological pathway information through analyses like Genome-Wide Association Network Analysis (GWANA) reveals enriched pathways that are central to lipid metabolism. [9] The identification of such compensatory mechanisms and therapeutic targets is crucial for developing strategies to manage lipid disorders.
References
Section titled “References”[1] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-169.
[2] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 12, 2008, pp. 149-51.
[3] Sabatti, C., et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, 2008.
[4] 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.”J Biol Chem, vol. 275, 2000, pp. 13300–13306.
[5] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, 2007.
[6] Gotto Jr, A. M., Brinton, E. A. “Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update.”J Am Coll Cardiol, 2004.
[7] 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.” Am. Heart J, vol. 155, no. 5, 2008, p. 823.
[8] Pollin, T. I. et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, no. 5904, 2008, pp. 1088-1092.
[9] Aulchenko, Y. S. et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 12, 2008, pp. 1492-1497.
[10] Hegele, R. A. et al. “The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree.”Arterioscler Thromb Vasc Biol, vol. 20, no. 1, 2000, pp. 217-222.
[11] Burkhardt, R. et al. “Common SNPs in HMGCR in Micronesians and Caucasians associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, vol. 28, no. 10, 2008, pp. 1891-1897.
[12] 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.
[13] 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, p. e1000282.