Free Cholesterol In Vldl
Introduction
Section titled “Introduction”Free cholesterol in very low-density lipoprotein (VLDL) refers to the unesterified cholesterol molecules embedded within the surface monolayer of VLDL particles. VLDL is a type of lipoprotein synthesized primarily in the liver, serving as the main transport vehicle for triglycerides, which are fats derived from dietary intake or synthesized endogenously. While VLDL is rich in triglycerides, it also contains cholesterol, phospholipids, and apolipoproteins, which are crucial for its structure and function. The free cholesterol component is essential for maintaining the fluidity and integrity of the VLDL particle’s surface, facilitating interactions with enzymes and receptors in the bloodstream.
Biological Basis
Section titled “Biological Basis”The liver produces VLDL particles, which are then secreted into the bloodstream. These particles deliver triglycerides to various tissues for energy or storage. During circulation, VLDL undergoes enzymatic modification by lipoprotein lipase (LPL), which hydrolyzes triglycerides, reducing the size of the VLDL particle and increasing the relative proportion of cholesterol. This process transforms VLDL into intermediate-density lipoprotein (IDL) and subsequently into low-density lipoprotein (LDL). Free cholesterol on the VLDL surface is critical for maintaining the particle’s structure and allowing it to interact with other molecules and cell surfaces during its metabolic journey. Genetic factors significantly influence the regulation of circulating lipid levels, including those within VLDL.[1]
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of VLDL and the cholesterol it carries are a key aspect of dyslipidemia, a condition characterized by abnormal concentrations of lipids in the blood. Dyslipidemia, including high levels of LDL cholesterol and triglycerides, is a major risk factor for cardiovascular diseases, such as coronary artery disease.[2]Understanding the role of free cholesterol in VLDL contributes to a comprehensive view of lipid metabolism and its impact on cardiovascular health. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with lipid concentrations, including those influencing LDL cholesterol and triglycerides, which are metabolically linked to VLDL.[1] For example, genes such as LPL and MLXIPLhave been associated with plasma triglyceride levels, whileHMGCR, LDLR, PCSK9, CELSR2, PSRC1, and SORT1 are linked to LDL cholesterol concentrations. [1]These genetic insights highlight the complex interplay of pathways that regulate lipoprotein levels.
Social Importance
Section titled “Social Importance”Cardiovascular diseases, often exacerbated by dyslipidemia, represent a significant global health burden, contributing to millions of deaths annually.[2] The high heritability of circulating lipid levels underscores the importance of genetic research in identifying individuals at higher risk and developing targeted interventions. [1]By elucidating the genetic and biological factors influencing VLDL cholesterol, researchers aim to improve diagnostic tools, preventive strategies, and therapeutic approaches to manage dyslipidemia and reduce the incidence of cardiovascular disease worldwide. This knowledge is crucial for public health initiatives focused on promoting heart health and addressing the societal impact of these prevalent conditions.
Variants
Section titled “Variants”Genetic variants play a significant role in modulating an individual’s lipid profile, including the levels of free cholesterol within very-low-density lipoproteins (VLDL). Several genes are central to the production, metabolism, and clearance of VLDL, with specific single nucleotide polymorphisms (SNPs) influencing these complex processes. For instance, theAPOE-APOC1gene cluster is critical for the catabolism of triglyceride-rich lipoproteins. Apolipoprotein E, encoded byAPOE, acts as a ligand for cellular receptors, facilitating the uptake of VLDL remnants by the liver. The variant rs1065853 in this region can impact the efficiency of this clearance, thereby affecting circulating VLDL levels and their free cholesterol content..[3] Similarly, APOBencodes apolipoprotein B, the primary structural protein of VLDL, essential for its assembly and secretion from the liver; variations likers676210 can influence VLDL particle number and size. TheLPL gene, with variants such as rs117026536 , encodes lipoprotein lipase, an enzyme crucial for hydrolyzing triglycerides in VLDL, directly affecting their remodeling and the eventual release of free cholesterol. TheLPA and LPAL2 genes, including variants rs10455872 , rs73596816 , and rs117733303 , are primarily known for their roles in lipoprotein(a) metabolism, but their genetic variations can also indirectly influence overall lipid transport dynamics and VLDL characteristics..[4]
Other genes exert their influence on VLDL free cholesterol through broader metabolic regulation.GCKRencodes glucokinase regulatory protein, which controls glucokinase activity—a key enzyme in hepatic glucose metabolism that impacts de novo lipogenesis. Thers1260326 variant in GCKRis associated with elevated triglyceride levels, suggesting an effect on VLDL production and, consequently, its free cholesterol composition..[4] MLXIPL, also known as ChREBP, is a transcription factor that orchestrates the expression of genes involved in fatty acid synthesis and glucose metabolism in the liver. Thers34060476 variant in MLXIPLcan alter this regulatory activity, leading to changes in hepatic lipid production and the amount of free cholesterol loaded into VLDL particles. Furthermore,TRIB1AL (Tribbles homolog 1), with its variant rs28601761 , plays a role in regulating lipid metabolism by affecting the stability of key transcription factors involved in hepatic lipid synthesis and VLDL secretion, thereby influencing VLDL-cholesterol and triglyceride levels..[4]
Finally, some genes, while not directly involved in VLDL assembly, can still impact lipid homeostasis through diverse cellular functions. ZPR1 (Zinc Finger Protein, Recombinant 1), containing the variant rs964184 , is involved in protein degradation and cell cycle regulation. While a direct link to VLDL free cholesterol is less defined, its role in maintaining cellular health and protein turnover can indirectly affect metabolic pathways involved in hepatic lipid processing or lipoprotein assembly. Similarly,DOCK7 (Dedicator of Cytokinesis 7), with variant rs11207997 , is primarily recognized for its functions in neuronal development and cytoskeleton dynamics. However, genetic studies have identified associations between DOCK7variants and various lipid traits, suggesting an indirect role in metabolic regulation, possibly through pathways influencing adipose tissue function, energy balance, or hepatic lipid handling, which could ultimately affect VLDL composition and free cholesterol levels..[4]
Key Variants
Section titled “Key Variants”Causes
Section titled “Causes”Genetic Architecture of Lipoprotein Regulation
Section titled “Genetic Architecture of Lipoprotein Regulation”The levels of circulating lipids, including those found within very low-density lipoprotein (VLDL) particles, are highly heritable traits, with studies establishing a strong genetic component influencing their concentrations[1]. [5] Dyslipidemia, encompassing alterations in VLDL cholesterol, often arises from a complex polygenic basis, where common variants at numerous loci contribute to an individual’s overall lipid profile. [6] Beyond polygenic risk, Mendelian forms of dyslipidemias, characterized by extreme lipid values, have revealed the involvement of specific genes and proteins crucial for lipid metabolism. [1]
Several genes and genetic regions have been identified that influence the metabolism of lipoproteins, thereby impacting VLDL composition. For instance, variants in genes critical for triglyceride metabolism, such asMLXIPL, ANGPTL3, and the APOA5-APOA4-APOC3-APOA1cluster, are associated with plasma triglyceride levels[7], [8]. [5] Since VLDL is the primary carrier of triglycerides, these genetic variations can directly impact VLDL particle number and composition, including its cholesterol content. Other genes, like LPL, which encodes lipoprotein lipase responsible for hydrolyzing triglycerides in VLDL, and theAPOE-APOC1-APOC4-APOC2 cluster, involved in VLDL remnant uptake, are also key determinants of VLDL processing and clearance, influencing its overall cholesterol load [1], [8]. [5]
Environmental and Lifestyle Influences on Lipid Homeostasis
Section titled “Environmental and Lifestyle Influences on Lipid Homeostasis”Environmental and lifestyle factors are critical determinants of overall lipid profiles, including those influencing VLDL composition. Dietary habits, physical activity, and other lifestyle choices can significantly modulate hepatic lipid synthesis and secretion, directly impacting the quantity and cholesterol content of VLDL particles. Studies consistently highlight that blood lipoprotein and triglyceride levels are significant risk factors for cardiovascular disease, which are widely recognized as being influenced by environmental exposures[6]. [5]
Socioeconomic factors and geographic influences are often linked to specific lifestyle and dietary patterns, which can further contribute to variations in lipid metabolism across populations. While specific details for VLDL cholesterol are not provided, population-based studies frequently adjust for factors like “enrolling center”.[5]implicitly accounting for regional differences in environment and lifestyle that affect overall lipid levels. These external factors can trigger or exacerbate genetically predisposed tendencies towards dyslipidemia, demonstrating a complex gene-environment interaction that shapes an individual’s VLDL profile.
Comorbidities, Age, and Pharmacological Effects
Section titled “Comorbidities, Age, and Pharmacological Effects”The composition of VLDL, including its cholesterol content, is significantly influenced by various physiological factors, comorbidities, and medication effects. Age is a well-established factor influencing lipid levels, with researchers routinely adjusting for “age and age2” in analyses of lipoprotein concentrations to account for age-related changes.[5] As individuals age, changes in metabolic pathways can lead to altered VLDL production and clearance.
Comorbidities, such as type 2 diabetes, are strongly linked to dyslipidemia and can substantially impact VLDL metabolism. Many genome-wide association studies investigating lipid loci have included or been enriched with individuals having type 2 diabetes, underscoring the profound effect of this condition on lipid profiles. [1]Diabetes can lead to increased hepatic VLDL production and impaired VLDL clearance, affecting its cholesterol content. Furthermore, pharmacological interventions, particularly lipid-lowering therapies, are potent modifiers of lipid levels. Individuals on such medications are typically excluded from genetic association analyses to ensure the study of untreated lipid concentrations, highlighting their significant impact on lipoprotein profiles, including VLDL[6]. [5]
Biological Background
Section titled “Biological Background”Very Low-Density Lipoproteins (VLDL) are a type of lipoprotein particle synthesized in the liver, primarily responsible for transporting triglycerides and cholesterol to various tissues throughout the body. The level of free cholesterol within VLDL particles is a key indicator of lipid metabolism and overall cardiovascular health, as dysregulation can contribute to the development of atherosclerosis and related conditions.[8]Understanding the intricate molecular, genetic, and physiological processes that govern VLDL metabolism and its cholesterol content is crucial for comprehending its role in disease.
Lipoprotein Dynamics and Systemic Lipid Transport
Section titled “Lipoprotein Dynamics and Systemic Lipid Transport”Lipoproteins are complex particles composed of lipids and proteins that facilitate the transport of hydrophobic fats, such as cholesterol and triglycerides, through the aqueous environment of the bloodstream. VLDL particles, rich in triglycerides, are synthesized and secreted by the liver, acting as the initial carriers for newly synthesized lipids. [9] As VLDL circulates, it unloads triglycerides to peripheral tissues, transforming into VLDL remnants and eventually into Low-Density Lipoproteins (LDL), which are a major carrier of cholesterol to cells. [8] Conversely, High-Density Lipoproteins (HDL) are involved in reverse cholesterol transport, removing excess cholesterol from tissues and returning it to the liver. [8]The balance between these lipoprotein classes and their lipid cargo, including free cholesterol, is critical for maintaining metabolic homeostasis and preventing the cumulative deposition of cholesterol in arteries, a hallmark of atherosclerosis.[8]
Disruptions in lipoprotein metabolism, often leading to elevated levels of LDL cholesterol or triglycerides, are strongly associated with increased risk of coronary artery disease (CAD) and stroke.[8] For instance, high concentrations of LDL cholesterol significantly increase CAD risk, while high HDL cholesterol concentrations are protective. [8]The protein apolipoprotein C-III (APOC3), secreted by the liver and intestines, is a component of both HDL and apoB-containing lipoproteins like VLDL, and plays a critical role in regulating their metabolism. [9] It impairs the catabolism and hepatic uptake of apoB-containing lipoproteins, while also appearing to enhance HDL catabolism. [9] A null mutation in human APOC3has been shown to result in a favorable plasma lipid profile and protection against cardiovascular events.[9]
Molecular Pathways Governing Cholesterol and Triglyceride Metabolism
Section titled “Molecular Pathways Governing Cholesterol and Triglyceride Metabolism”The cellular and molecular pathways that regulate cholesterol and triglyceride synthesis and breakdown are central to determining the free cholesterol content of VLDL. Cholesterol biosynthesis involves a series of enzymatic steps, with a key early step catalyzed by mevalonate kinase, encoded byMVK. [8] Another crucial enzyme, HMG-CoA reductase, encoded by HMGCR, also catalyzes an early step in cholesterol biosynthesis, and its activity is tightly regulated. [8] Genetic variations in HMGCR can influence LDL cholesterol levels by affecting processes like alternative splicing of exon 13. [10] The synthesis of triglycerides, which are the primary lipid component of VLDL, is influenced by proteins like MLXIPL, which binds to and activates specific motifs in the promoters of triglyceride synthesis genes.[8]
Beyond synthesis, the catabolism and uptake of lipoproteins are equally important. PCSK9(Proprotein Convertase Subtilisin/Kexin type 9) is a key enzyme that post-transcriptionally regulates the Low-Density Lipoprotein Receptor (LDLR), accelerating its degradation. [11] This degradation reduces the number of LDLR available to clear LDL cholesterol from the blood, thereby influencing overall cholesterol levels. [11] Other proteins like ANGPTL4are known to inhibit lipoprotein lipase, an enzyme critical for the breakdown of triglycerides in VLDL.[6]These intricate regulatory networks ensure that lipids, including free cholesterol, are appropriately packaged, transported, and delivered within VLDL and other lipoprotein particles.
Genetic Influences on Lipoprotein Levels
Section titled “Genetic Influences on Lipoprotein Levels”Genetic factors play a significant role in determining individual differences in circulating lipid levels, including the free cholesterol in VLDL.[12] Genome-Wide Association Studies (GWAS) have identified numerous loci associated with variations in HDL cholesterol, LDL cholesterol, and triglycerides, providing insights into the polygenic nature of dyslipidemia. [6] Genes such as APOA5-APOA4-APOC3-APOA1 and APOE-APOC1-APOC4-APOC2 are prominent examples of gene clusters influencing lipid metabolism. [12] For instance, common variants in genes like PCSK9are associated with low LDL cholesterol levels and protection against coronary heart disease, while mutations inPCSK9 can also cause autosomal dominant hypercholesterolemia. [13]
Other genetic loci have also been linked to specific lipid phenotypes. Variants near TRIB1, MLXIPL, and ANGPTL3have been associated with plasma triglyceride levels.[5] The genes TIMD4 and HAVCR1 at locus 5q23, known as phosphatidylserine receptors on macrophages, and MAFB at 20q12, a transcription factor, have been associated with LDL cholesterol levels. [6] Transcription factors like HNF4A and HNF1A also influence plasma cholesterol levels, with specific variants in HNF1Aimpacting lipoprotein variation.[6] These genetic insights highlight the complex interplay of multiple genes in shaping an individual’s lipid profile and, consequently, the composition of lipoproteins like VLDL.
Regulatory Proteins and Receptor Interactions in Lipid Homeostasis
Section titled “Regulatory Proteins and Receptor Interactions in Lipid Homeostasis”The precise control of lipoprotein metabolism relies heavily on the coordinated action of various regulatory proteins, enzymes, and receptors. Apolipoproteins, such asAPOC3, are integral components of lipoprotein particles, modulating their structure and interaction with enzymes and receptors.[9] As a component of VLDL, APOC3 directly impacts the catabolism and hepatic uptake of these particles, thus influencing the overall levels of VLDL and its associated cholesterol. [9]Enzymes like lipoprotein lipase (LPL), inhibited by ANGPTL4, are crucial for hydrolyzing triglycerides within VLDL, allowing for the release of fatty acids to tissues and the subsequent remodeling of VLDL particles. [6]
Receptors, particularly the LDLR, play a pivotal role in the clearance of cholesterol-rich lipoproteins from circulation. The activity and abundance of LDLR are tightly regulated, notably by PCSK9, which promotes LDLR degradation, thereby diminishing the liver’s capacity to remove LDL and VLDL remnants. [11] Other proteins like GALNT2, a glycosyltransferase, could potentially modify lipoproteins or their receptors, further influencing their metabolism. [8]These molecular interactions, occurring predominantly in the liver, are fundamental to maintaining lipid homeostasis and directly impact the amount of free cholesterol carried by VLDL and other circulating lipoproteins.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Transcriptional Control of Lipid Synthesis and Degradation
Section titled “Transcriptional Control of Lipid Synthesis and Degradation”The regulation of lipid metabolism, including the synthesis of triglycerides and cholesterol, is tightly controlled at the transcriptional level, influencing the availability of lipids for very low-density lipoprotein (VLDL) assembly. The geneMLXIPL (also known as ChREBP) encodes a protein that plays a crucial role in this process by binding to and activating specific motifs within the promoters of genes responsible for triglyceride synthesis.[8] This direct transcriptional activation contributes to the overall pool of triglycerides available for incorporation into VLDL particles. Similarly, the transcription factor SREBP2 governs the expression of genes involved in both cholesterol biosynthesis and degradation, ensuring a balanced cellular cholesterol supply. [8]
This coordinated transcriptional control extends to genes like MVK and MMAB, which share a common promoter and are both regulated by SREBP2. [8]Such co-regulation suggests a finely tuned feedback loop, where the cellular demand for cholesterol dictates the simultaneous activation or repression of both synthetic and catabolic pathways. The activation of triglyceride synthesis byMLXIPL and the broader regulation of cholesterol metabolism by SREBP2represent key nodes in a complex regulatory network that ultimately dictates the lipid content and composition of circulating lipoproteins, including free cholesterol within VLDL.
Enzymatic Pathways in Cholesterol Homeostasis
Section titled “Enzymatic Pathways in Cholesterol Homeostasis”Cholesterol homeostasis relies on a delicate balance between its synthesis and degradation, involving specific enzymatic steps that are critical for maintaining lipid concentrations. The gene MVK encodes mevalonate kinase, an enzyme that catalyzes an early, rate-limiting step in the cholesterol biosynthesis pathway. [8] Its activity is essential for generating the precursors necessary for cholesterol production, thereby directly influencing the cellular cholesterol pool available for VLDL packaging. In contrast, the gene MMAB encodes a protein that participates in a metabolic pathway responsible for cholesterol degradation. [8]
The co-localization and shared promoter of MVK and MMAB, both under the transcriptional control of SREBP2, highlight an integrated regulatory mechanism for cholesterol flux. [8] This hierarchical regulation ensures that the cellular machinery can rapidly adjust cholesterol levels by simultaneously modulating both its production and breakdown. Such precise metabolic regulation is vital for preventing excessive accumulation or depletion of cholesterol, which has implications for the overall lipid profile and the cholesterol content of VLDL.
Systemic Regulators of Lipoprotein Metabolism
Section titled “Systemic Regulators of Lipoprotein Metabolism”Beyond direct synthesis and degradation, broader systemic regulators exert significant influence over overall lipid and lipoprotein metabolism.ANGPTL3 encodes a protein homolog that functions as a major regulator of lipid metabolism, as demonstrated in studies involving mice. [8] This broad regulatory role suggests that ANGPTL3can impact the processing and clearance of various lipoproteins, including VLDL, thereby affecting circulating free cholesterol levels.
Furthermore, rare genetic variants in ANGPTL4, a gene related to ANGPTL3, have been associated with altered concentrations of high-density lipoprotein (HDL) and triglycerides in humans.[8] These findings underscore the critical role of the ANGPTLfamily in orchestrating systemic lipid homeostasis. Their influence on triglyceride metabolism, in particular, is highly relevant to VLDL, as VLDL particles are rich in triglycerides and their metabolism is closely linked to the distribution of cholesterol among lipoproteins.
Post-Translational Modification and Receptor Interactions
Section titled “Post-Translational Modification and Receptor Interactions”The functional properties and clearance of lipoproteins, including VLDL, can be significantly influenced by post-translational modifications and their interactions with cellular receptors. The gene GALNT2 encodes a widely expressed glycosyltransferase, an enzyme responsible for attaching sugar moieties to proteins. [8] Through its enzymatic activity, GALNT2 could potentially modify the glycosylation patterns of lipoproteins themselves or the receptors that bind them.
Such modifications can alter the structural integrity, circulating half-life, or receptor recognition of lipoproteins, thereby impacting their metabolism and the delivery of their lipid cargo, including free cholesterol. Changes in glycosylation could affect the binding affinity of VLDL particles to lipoprotein receptors or modify the activity of enzymes involved in VLDL processing, representing a complex layer of regulatory control over systemic lipid concentrations and the fate of cholesterol within lipoproteins.
Clinical Relevance
Section titled “Clinical Relevance”Risk Stratification and Prognostic Implications
Section titled “Risk Stratification and Prognostic Implications”The concentration of free cholesterol within VLDL particles is intrinsically linked to overall VLDL metabolism and total cholesterol levels, both of which are critical components in cardiovascular risk assessment. Research indicates that genetic risk profiles, particularly those constructed for total cholesterol—a composite including VLDL cholesterol—significantly enhance the prediction of atherosclerosis and coronary heart disease (CHD) risk beyond traditional clinical factors like age, BMI, and sex.[1]This suggests that variations in VLDL cholesterol, including its free cholesterol content, contribute to an individual’s long-term cardiovascular prognosis and the likelihood of disease progression. Identifying individuals with specific genetic predispositions that influence VLDL cholesterol levels could allow for more personalized and earlier intervention strategies.
Furthermore, while low-density lipoprotein (LDL) cholesterol is a well-established driver of atherosclerosis, elevated triglyceride levels, predominantly carried by VLDL particles, are recognized as an additional, independent risk factor for cardiovascular disease.[8]Understanding the genetic determinants that modulate VLDL levels and composition, such as free cholesterol, therefore holds prognostic value for identifying high-risk individuals. These genetic insights can predict outcomes by highlighting individuals with a greater susceptibility to dyslipidemia and its associated cardiovascular complications, guiding targeted preventive measures.
Guiding Clinical Management and Therapeutic Approaches
Section titled “Guiding Clinical Management and Therapeutic Approaches”Insights into the genetic factors influencing VLDL components, including free cholesterol, have the potential to refine clinical management and treatment selection for dyslipidemia. Genome-wide association studies have identified numerous loci associated with lipid concentrations, including those influencing triglycerides, a major constituent of VLDL.[5] For instance, variants near genes like GALNT2, TRIB1, ANGPTL3, FADS1-FADS2-FADS3, and PLTPhave been linked to triglyceride levels.[5] A deeper understanding of how these genetic variations affect VLDL metabolism and cholesterol efflux could enable more personalized therapeutic strategies, potentially informing the selection of lipid-lowering therapies or dietary interventions that specifically target VLDL production or clearance.
Although direct therapeutic targets for free cholesterol in VLDL are not explicitly detailed, the broader context of VLDL regulation offers avenues for intervention. Monitoring strategies could be tailored to an individual’s genetic profile, allowing clinicians to track specific lipid parameters more closely in those predisposed to elevated VLDL or related dyslipidemias. Such genetic information could contribute to a more comprehensive understanding of a patient’s response to treatment, moving towards a more precise medicine approach in managing complex lipid disorders.
Genetic Architecture and Comorbid Associations
Section titled “Genetic Architecture and Comorbid Associations”The polygenic nature of dyslipidemia means that common genetic variants at numerous loci collectively contribute to variations in blood lipid concentrations, including those influencing VLDL components. Studies have identified approximately 30 distinct loci associated with lipoprotein concentrations, including those impacting triglycerides and total cholesterol, which are directly relevant to VLDL.[6] For example, specific gene regions such as TBL2 and MLXIPL, TRIB1, GALNT2, CILP2-PBX4, and ANGPTL3have been robustly associated with triglyceride levels.[5] These findings underscore the complex biological pathways involved in VLDL synthesis, catabolism, and lipid exchange, highlighting potential overlapping phenotypes with other metabolic conditions.
The genetic landscape of VLDL-associated traits also reveals connections to broader cardiovascular health. Identifying these genetic associations helps to unravel the intricate interplay between various lipid fractions and their impact on conditions like atherosclerosis and coronary artery disease. Understanding these genetic underpinnings can illuminate shared pathways with other metabolic comorbidities, such as insulin resistance or fatty liver disease, which often present with dyslipidemia characterized by elevated VLDL.
References
Section titled “References”[1] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, 2008, p. 19060911.
[2] Wallace, C., et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139-49.
[3] Reiner, AP. “Polymorphisms of the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.”Am J Hum Genet, 2008.
[4] Benjamin, EJ. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, 2007.
[5] Kathiresan, S et al. “Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.”Nat Genet, vol. 40, no. 2, 2008, pp. 189-197.
[6] Kathiresan, S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 5, 2009, pp. 56-65.
[7] Kooner, J. S., et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, vol. 40, no. 2, 2008, pp. 149-51.
[8] 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.
[9] Pollin, Timothy I., et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 326, no. 5957, 2009, pp. 1403-1406.
[10] 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. 29, no. 1, 2009, pp. 109-116.
[11] Maxwell, K. N., E. A. Fisher, and J. L. Breslow. “Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.” Proceedings of the National Academy of Sciences USA, vol. 102, no. 6, 2005, pp. 2069-2074.
[12] Aulchenko, Yurii S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nature Genetics, vol. 41, no. 1, 2009, pp. 47-55.
[13] Cohen, Jonathan C., et al. “Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.”New England Journal of Medicine, vol. 354, no. 12, 2006, pp. 1264-1272.