Cholesterol Esters In Medium Ldl
Cholesterol is a crucial lipid molecule essential for various biological functions, including maintaining cell membrane integrity, synthesizing steroid hormones, and producing vitamin D. In the human body, cholesterol is transported through the bloodstream within complex particles known as lipoproteins. Low-density lipoprotein (LDL) is one such class of lipoproteins, often colloquially termed “bad cholesterol” due to its well-established association with cardiovascular disease (CVD). Within LDL particles, cholesterol is predominantly stored and transported in the form of cholesterol esters. The specific concentration of cholesterol esters within medium-sized LDL particles is a key aspect of lipid metabolism, reflecting the dynamic processes of cholesterol synthesis, transport, and uptake.
Biological Basis
Section titled “Biological Basis”The levels of cholesterol esters within LDL particles are influenced by a complex interplay of genetic and environmental factors. Genetic variation significantly contributes to the observed differences in LDL cholesterol levels among individuals. [1]Numerous genes play critical roles in the synthesis, metabolism, and transport of cholesterol and lipoproteins. For instance, common single nucleotide polymorphisms (SNPs) in theHMGCR gene, which encodes 3-hydroxy-3-methylglutaryl coenzyme A reductase (a key enzyme in cholesterol synthesis), are associated with LDL-cholesterol levels and can affect the alternative splicing of its exon 13. [1]
Other genes implicated in lipid metabolism include CETP, LCAT, GALNT2, LPL, ABCA1, APOB, and LDLR, all of which have SNPs associated with various lipoprotein traits.[2] The PSRC1 and CELSR2 genes, located in a region on chromosome 1p13.3, have been strongly linked to LDL cholesterol levels, with a common allele (rs599839 ) associated with a significant increase in both non-fasting and fasting serum LDL. [3] Furthermore, mutations in PCSK9 have been shown to result in lower LDL cholesterol levels. [4]The composition and size of LDL particles, including the quantity of cholesterol esters they carry, are therefore under considerable genetic control.
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of LDL cholesterol, and specifically cholesterol esters within LDL, are a primary risk factor for the development and progression of cardiovascular diseases, including coronary artery disease.[3] Understanding the genetic determinants of cholesterol ester levels in medium LDL is clinically relevant for assessing an individual’s risk for CVD and for developing targeted preventive and therapeutic strategies. Pharmacological interventions, such as statins, primarily work by inhibiting HMGCR to reduce cholesterol synthesis and, consequently, lower LDL cholesterol levels. [1] The identification of specific genetic variants influencing these lipid traits provides valuable insights into the pathophysiology of dyslipidemia and potential avenues for drug development.
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of mortality and morbidity worldwide, with elevated cholesterol contributing to millions of deaths annually.[3] Research into the genetic and biological factors that influence cholesterol ester levels in medium LDL is of significant social importance. This knowledge can lead to improved public health outcomes through enhanced risk stratification, more effective prevention programs, and the development of personalized treatment approaches. Genome-wide association studies (GWAS) have been instrumental in identifying numerous genetic loci associated with lipid concentrations, underscoring the polygenic nature of dyslipidemia and the complex biological pathways involved. [4]These findings contribute to a broader understanding of metabolic health and the societal burden of cardiovascular disease.
Limitations
Section titled “Limitations”Phenotypic Definition and Statistical Modeling
Section titled “Phenotypic Definition and Statistical Modeling”The definition of “cholesterol esters in medium ldl” as a phenotype in these studies relies on standardized residuals derived after regression adjustment for factors like age, age squared, sex, and ancestry-informative principal components.[5] While this standardization helps to normalize data for genetic association analysis, it means that the identified genetic effects pertain to these adjustedlipoprotein concentrations rather than their raw physiological levels. Therefore, direct interpretation of findings in terms of absolute concentrations or clinical thresholds requires careful consideration of these statistical transformations.
Furthermore, the assumption of an additive mode of inheritance for genotypic effects simplifies complex biological realities and might overlook non-additive genetic interactions or epistatic effects that contribute to lipoprotein levels.[5]Although linear mixed-effects models were employed to account for relatedness and a random polygenic effect allowing for residual heritability, a substantial portion of the heritable variation in cholesterol esters in medium ldl may still remain unexplained by the specific common variants identified.[5] This concept of “missing heritability” underscores the current limitations in fully elucidating the genetic architecture of lipid traits, suggesting roles for rarer variants, structural variations, or more complex genetic interactions not captured by this design.
Generalizability and Ancestral Diversity
Section titled “Generalizability and Ancestral Diversity”The studies involved participants from cohorts such as FHS, SUVIMAX, LOLIPOP, and InCHIANTI, each representing specific populations. [5] While the inclusion of ten ancestry-informative principal components in the statistical models aims to control for population stratification within these groups, the generalizability of these findings to globally diverse populations remains an important consideration. [5] Genetic architectures and allele frequencies can vary significantly across different ancestral groups, meaning that variants identified as significant in predominantly European or other specific populations might not hold the same effect sizes or even associations in others.
This limitation implies that the identified genetic loci for cholesterol esters in medium ldl may not fully capture the genetic diversity contributing to this trait across all human populations. Phenotype variability or environmental differences between unrepresented ancestries could also introduce further complexities. Consequently, broader replication efforts across a wider spectrum of global populations are essential to confirm and expand upon these initial findings and to ensure equitable applicability of genetic insights.
Environmental and Gene-Environment Confounders
Section titled “Environmental and Gene-Environment Confounders”While critical adjustments were made for demographic factors such as age, age squared, and sex, the studies may not fully account for the myriad of environmental and lifestyle factors that profoundly influence cholesterol esters in medium ldl levels.[5]Unmeasured or residual confounding by elements like dietary patterns, physical activity levels, smoking status, alcohol consumption, socioeconomic factors, or the use of medications could obscure or modify genetic effects. These unexamined environmental variables can interact with genetic predispositions, leading to a complex interplay that is challenging to fully dissect in current study designs.
The absence of comprehensive environmental phenotyping limits the ability to identify significant gene-environment interactions, which are known to play a crucial role in multifactorial traits like dyslipidemia. Disentangling these complex relationships is vital for developing personalized prevention and treatment strategies. Without a complete understanding of these environmental influences and their interactions with genetic factors, the full impact of identified variants on cholesterol esters in medium ldl levels, and thus their predictive utility, remains partially understood.
Variants
Section titled “Variants”Genetic variations play a crucial role in determining an individual’s cholesterol metabolism, particularly impacting the levels and composition of cholesterol esters within medium low-density lipoprotein (LDL) particles. A network of genes, including those involved in lipoprotein assembly, uptake, and cholesterol synthesis, contributes to these complex processes. Specific single nucleotide polymorphisms (SNPs) within these genes can subtly or significantly alter their function, leading to variations in lipid profiles.
Key variants in lipid regulation include those associated with core pathways for LDL synthesis and clearance. The genetic locus encompassing CELSR2, PSRC1, and SORT1 on chromosome 1 contains *rs646776 *, which has been consistently linked to LDL cholesterol levels. SORT1in particular influences the hepatic secretion of very-low-density lipoprotein (VLDL), the precursor to LDL, thereby impacting the amount of cholesterol esters in circulating medium LDL particles.[2] Similarly, the LDLR gene, encoding the LDL receptor responsible for clearing LDL from the bloodstream, features variants like *rs6511720 * that can alter its efficiency, leading to changes in circulating LDL and its cholesterol ester content. [2] PCSK9 regulates LDLR levels, and the *rs11591147 * variant can affect LDLR degradation, thereby influencing LDL clearance and the cholesterol ester load within medium LDL. [2] Furthermore, APOB, which forms the structural backbone of LDL, has variants such as *rs563290 *that can impact lipoprotein assembly and metabolism, directly influencing cholesterol ester content.[2] The HMGCR gene, encoding the rate-limiting enzyme in cholesterol biosynthesis, contains the *rs12916 * variant, which can affect cholesterol production in the liver and, consequently, the levels and esterification of cholesterol in LDL. [2]
Other significant variants influence diverse aspects of lipid metabolism and transport. The ABCG8 gene, involved in the excretion of sterols from the liver and intestine, includes the *rs4245791 * variant, which can modulate cholesterol absorption and excretion, thereby affecting systemic cholesterol levels and the esterification of cholesterol in medium LDL. [2] FADS2, an enzyme critical for synthesizing polyunsaturated fatty acids, harbors the *rs174574 * variant, which can alter the fatty acid composition available for esterification, indirectly impacting the cholesterol ester profile of lipoproteins. [2] Moreover, the *rs58542926 * variant in TM6SF2 influences VLDL secretion from the liver; its minor allele is associated with reduced VLDL secretion, which can lead to lower circulating LDL cholesterol and alterations in the cholesterol ester content of medium LDL. [2]
Beyond direct lipid pathways, some genes exert more pleiotropic effects on lipid profiles. The ABO blood group gene, with variants like *rs635634 *, has been associated with lipid levels, potentially through its influence on systemic inflammatory processes or other circulating factors that modulate lipoprotein metabolism, indirectly affecting cholesterol esters in medium LDL.[2] Similarly, loci such as HNRNPA1P67 - RNU4ATAC9P, containing the *rs181948526 *variant, represent regions that may influence gene regulation, alternative splicing, or non-coding RNA functions. While not directly encoding metabolic enzymes, variations in these regions can exert indirect or subtle regulatory effects that ultimately impact lipid homeostasis and the characteristics of cholesterol esters in medium LDL particles.[2]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Lipoprotein Structure and Classification
Section titled “Lipoprotein Structure and Classification”Cholesterol esters are a primary form of cholesterol storage and transport in the body, representing cholesterol molecules esterified with a fatty acid. Within the circulatory system, these hydrophobic molecules are packaged into lipoprotein particles, which are complex aggregates of lipids and proteins designed for lipid transport. Lipoproteins are broadly classified based on their density and size, which also dictates their lipid and apolipoprotein composition. Key classes include very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).[5]Medium low-density lipoprotein (LDL) refers to a specific subfraction within the broader LDL class, characterized by its particular size and density, distinguishable from other LDL subtypes such as small dense LDL. The apolipoproteins_APOA-I_, _APOB_, _APOC-III_, and _APOE_are crucial protein components that stabilize lipoprotein structure, serve as enzyme cofactors, or act as ligands for receptor binding, all contributing to the metabolic fate of these particles.[5]
Defining and Measuring Lipoprotein Subfractions
Section titled “Defining and Measuring Lipoprotein Subfractions”The precise definition of lipoprotein subfractions, including medium LDL, is rooted in their physical properties that allow for their separation and quantification. Measurement approaches for lipoprotein particle concentrations, encompassing low-, high-, intermediate-, and very low-density lipoproteins, often utilize advanced techniques such as nuclear magnetic resonance (NMR) spectroscopy.[5]This method allows for the quantification of different lipoprotein particle sizes, providing a more detailed picture than total cholesterol or triglyceride levels alone. While the research notes the measurement of HDL2 and HDL3 cholesterol subfractions through chemical precipitation, similar operational definitions and criteria are applied to delineate LDL subfractions like medium LDL, albeit often employing different analytical platforms to achieve this detailed separation.[5] The presence and concentration of cholesterol esters within these specifically defined medium LDL particles contribute to the overall “LDL cholesterol” measurement, a widely recognized biomarker.
Clinical Terminology and Mechanistic Significance
Section titled “Clinical Terminology and Mechanistic Significance”The term “dyslipidemia” refers to abnormal levels of lipids in the blood, which can involve elevated total cholesterol, LDL cholesterol, or triglycerides, or reduced HDL cholesterol. The study context specifically highlights “polygenic dyslipidemia,” indicating that variations in multiple genes contribute to an individual’s lipid profile.[5] Understanding specialized phenotypes, such as the concentration of cholesterol esters within medium LDL, offers insights into underlying mechanisms of dyslipidemia. For example, the _GCKR_ P446L allele (rs1260326 ) is associated with increased concentrations of _APOC-III_, an apolipoprotein that inhibits triglyceride catabolism and is synthesized in the liver.[5] Similarly, the _LPA_coding single nucleotide polymorphism (SNP)rs3798220 is strongly associated with both LDL cholesterol and lipoprotein(a) levels, underscoring the genetic influence on these specific lipid components and particle concentrations, and thus on cardiovascular risk.[5]
Causes of Cholesterol Esters in Medium LDL
Section titled “Causes of Cholesterol Esters in Medium LDL”Primary Genetic Drivers of LDL Levels
Section titled “Primary Genetic Drivers of LDL Levels”The levels of cholesterol esters in medium low-density lipoprotein (LDL) are significantly influenced by a range of inherited genetic factors that regulate lipid metabolism. Key among these are variants in genes such asCELSR2-PSRC1-SORT1, APOB, LDLR, and HMGCR. These genes play fundamental roles in the synthesis, transport, and cellular uptake of cholesterol. For instance, LDLR encodes the LDL receptor, which is critical for clearing LDL particles from the bloodstream, while APOB is a major structural protein of LDL that facilitates its binding to the receptor. [2] Similarly, HMGCR is the rate-limiting enzyme in endogenous cholesterol synthesis, and the CELSR2-PSRC1-SORT1 gene cluster has been consistently linked to hepatic lipid processing and LDL clearance. [2] Variations in these well-established genetic loci contribute substantially to an individual’s predisposition to differing LDL levels by directly impacting these core metabolic pathways.
Novel Genetic Associations
Section titled “Novel Genetic Associations”Beyond established genes, ongoing research continues to uncover new genetic associations that contribute to variations in LDL cholesterol. Two such newly identified genetic loci include a variant, rs4844614 , located within an intron of the CR1L gene on chromosome 1, and rs5031002 within an intron of the AR gene on chromosome X. [2] While CR1L encodes a complement receptor protein, its specific metabolic function related to LDL cholesterol is not yet fully understood. [2] The rs5031002 variant, on the other hand, is located in the androgen receptor (AR) gene, which encodes a ligand-dependent transcription factor with diverse functions, including the regulation of circulating androgen levels. [2] These new associations highlight the complex genetic architecture underlying LDL levels and identify potential novel pathways involved in their regulation.
Gene-Hormone Interactions and Sex-Specific Effects
Section titled “Gene-Hormone Interactions and Sex-Specific Effects”The impact of genetic factors on LDL cholesterol can be intricately linked with an individual’s internal hormonal environment, demonstrating clear gene-environment interactions. The rs5031002 variant in the AR gene provides a compelling example of such an interaction. Since the ARgene controls circulating androgen levels, and alterations in these hormone levels are associated with sex-specific dyslipidemias, this variant shows a distinct influence.[2] This low-frequency variant is associated with a marked increase in LDL cholesterol, predominantly observed in males. [2]While a similar effect size was noted in a rare female individual homozygous for the minor allele, the stronger manifestation in males suggests that the genetic predisposition fromAR interacts significantly with male hormonal profiles to elevate LDL, illustrating how intrinsic biological factors like sex hormones can modulate the phenotypic expression of specific genetic variants. [2]
Biological Background
Section titled “Biological Background”Lipoprotein Structure and Function in Cholesterol Transport
Section titled “Lipoprotein Structure and Function in Cholesterol Transport”Low-density lipoproteins (LDL) are complex particles critical for transporting cholesterol throughout the bloodstream, primarily delivering cholesterol esters to peripheral tissues. Cholesterol esters, formed by the esterification of cholesterol with a fatty acid, are more hydrophobic than free cholesterol, allowing for their efficient packaging within the core of lipoprotein particles . Further along this pathway,MVK (mevalonate kinase) catalyzes an early step in cholesterol production, while MMAB encodes a protein involved in cholesterol degradation, highlighting the coordinated processes of synthesis and catabolism. [6]Lipoprotein metabolism also involves enzymes likeLCAT (lecithin:cholesterolacyltransferase), crucial for esterifying free cholesterol within high-density lipoproteins (HDL), a process that subsequently influences cholesterol transfer to other lipoproteins, including medium LDL.[7]The catabolism of triglyceride-rich lipoproteins is influenced byAPOC3(apolipoprotein C-III), where a null mutation can lead to a favorable plasma lipid profile, demonstrating its role in lipid clearance and processing.[8]
Central to the uptake of cholesterol-rich lipoproteins, such as LDL, is the LDLR(low-density lipoprotein receptor), which mediates the endocytosis of these particles into cells. The availability and functionality ofLDLR are critically regulated by PCSK9 (proprotein convertase subtilisin/kexin type 9), an enzyme that promotes the lysosomal degradation of the LDLR, thereby reducing the cell’s capacity to clear LDL from circulation. [9] This post-translational control by PCSK9 represents a crucial checkpoint in determining plasma LDL-cholesterol concentrations. Hepatic lipase, encoded by LIPC, also plays a significant role in the catabolism of HDL and chylomicron remnants, affecting the overall lipid profile and indirectly the composition and levels of cholesterol esters in medium LDL.[5] These pathways collectively form a dynamic network dictating cholesterol ester homeostasis.
Transcriptional and Post-Translational Regulation of Lipid Homeostasis
Section titled “Transcriptional and Post-Translational Regulation of Lipid Homeostasis”Lipid homeostasis is tightly controlled at both transcriptional and post-translational levels, involving complex signaling cascades and feedback loops. Transcription factors such as SREBP2 (sterol regulatory element-binding protein 2) regulate the expression of genes involved in cholesterol biosynthesis, including MVK and MMAB, thereby linking cellular sterol levels to the transcriptional machinery. [6] Another important transcriptional regulator is MLXIPL(MLX interacting protein like), which binds and activates specific motifs in the promoters of triglyceride synthesis genes, influencing the production of these key lipid components.[6]Genetic variants, such as common single nucleotide polymorphisms (SNPs) inHMGCR, can impact the alternative splicing of its mRNA, specifically affecting exon 13, which may alter the enzyme’s activity or expression and thus influence LDL-cholesterol levels. [1]
Post-translational modifications and protein-protein interactions provide another layer of regulation, critically modulating the activity and stability of key enzymes and receptors. For instance, PCSK9 exerts its control over LDLR by accelerating its degradation in a post-endoplasmic reticulum compartment, essentially diminishing the receptor’s capacity to internalize LDL particles. [9] This mechanism illustrates a potent feedback loop where PCSK9 activity indirectly controls the amount of circulating LDL, serving as a significant regulatory point in cholesterol metabolism. The activity of LIPC is also subject to regulatory mechanisms, with promoter variants influencing its expression and, consequently, hepatic lipase activity and HDL cholesterol levels. [5]
Fatty Acid Metabolism and Inter-Lipoprotein Dynamics
Section titled “Fatty Acid Metabolism and Inter-Lipoprotein Dynamics”Fatty acid metabolism profoundly influences the composition and dynamics of lipoproteins, including the esterification of cholesterol. The FADS1-FADS2-FADS3gene cluster encodes fatty acid desaturases, enzymes critical for converting polyunsaturated fatty acids into various cell signaling metabolites, such as arachidonic acid.[5]Variations within this cluster are associated with the fatty acid composition in phospholipids and have a significant impact on both HDL cholesterol and triglyceride levels, illustrating a direct crosstalk between fatty acid synthesis and lipoprotein profiles.[5] Specifically, alleles associated with increased FADS1 and FADS3 expression lead to higher HDL cholesterol and lower triglycerides, demonstrating their role in flux control within lipid metabolic pathways. [5]
Beyond desaturases, other proteins like ANGPTL3(angiopoietin-like protein 3) emerge as major regulators of lipid metabolism, impacting the systemic availability and processing of various lipoprotein classes.[6] Rare variants in ANGPTL4, a related gene, have also been associated with altered HDL and triglyceride concentrations, further underscoring the complex network interactions that govern lipoprotein composition and function.[6]These angiopoietin-like proteins often modulate the activity of lipoprotein lipase, an enzyme central to triglyceride hydrolysis, thereby indirectly affecting the availability of fatty acids for esterification and influencing the overall lipid environment, including cholesterol esters in medium LDL.
Genetic Modulators and Disease-Relevant Mechanisms in Dyslipidemia
Section titled “Genetic Modulators and Disease-Relevant Mechanisms in Dyslipidemia”Genetic variations frequently lead to pathway dysregulation, contributing to dyslipidemia and cardiovascular disease risk, making these pathways crucial therapeutic targets. A null mutation in humanAPOC3, for example, is associated with a favorable plasma lipid profile and apparent cardioprotection, by improving triglyceride metabolism and lipoprotein clearance.[8] Similarly, sequence variations in PCSK9that result in reduced function or lower expression are linked to lower LDL cholesterol levels and protection against coronary heart disease.[10] These genetic insights highlight PCSK9 as a significant therapeutic target for managing hypercholesterolemia.
Moreover, common genetic variants in HMGCR influence LDL-cholesterol levels by affecting the alternative splicing of exon 13, potentially altering enzyme activity or stability. [1] This subtle genetic modulation of a core metabolic enzyme underscores the sophisticated regulatory mechanisms that can predispose individuals to dyslipidemia. The FADS1-FADS2-FADS3gene cluster, through its influence on polyunsaturated fatty acid composition and downstream lipoprotein levels, also represents a locus where genetic variants contribute to polygenic dyslipidemia, impacting both HDL cholesterol and triglycerides.[5] Understanding these genetic modulators and their systems-level effects on pathway crosstalk is essential for identifying emergent properties of lipid metabolism and developing targeted therapies for dyslipidemia.
Clinical Relevance
Section titled “Clinical Relevance”Role in Cardiovascular Disease Pathogenesis
Section titled “Role in Cardiovascular Disease Pathogenesis”Elevated levels of low-density lipoprotein cholesterol (LDL-C), which primarily transports cholesterol esters in medium LDL particles, are a fundamental driver of atherosclerosis, a chronic inflammatory process leading to the cumulative deposition of cholesterol in arterial walls.[6]This pathological process is the primary underlying cause of coronary artery disease (CAD) and stroke, which are leading causes of morbidity, mortality, and disability globally.[6]Consistent epidemiological evidence demonstrates a strong association between high LDL-C concentrations and an increased risk of cardiovascular disease incidence, with estimates suggesting that each 1% decrease in LDL cholesterol concentrations can reduce the risk of coronary heart disease by approximately 1%.[6] The global health burden is substantial, as elevated cholesterol, largely driven by LDL-C, is estimated to contribute to 4.4 million deaths annually worldwide. [3]
Genetic Influences on LDL Cholesterol and Risk Stratification
Section titled “Genetic Influences on LDL Cholesterol and Risk Stratification”Recent genome-wide association studies (GWAS) have identified numerous genetic loci influencing LDL cholesterol levels, offering insights into inter-individual variability and providing tools for enhanced risk stratification. [4] For instance, common genetic variations in regions near CELSR2-PSRC1-SORT1 on chromosome 1p13.3 are strongly associated with LDL cholesterol concentrations, with certain alleles linked to increased LDL levels and a heightened risk of CAD. [3] Other genes such as APOB, LDLR, and HMGCR also have established roles, with variants like rs3846662 in HMGCR affecting LDL-C levels, potentially through alternative splicing. [2]Leveraging these genetic insights, genetic risk scores can be constructed, which have shown prognostic value by improving the classification of individuals at risk for dyslipidemia and coronary heart disease beyond traditional clinical factors like age, sex, and body mass index.[11]
Clinical Applications in Patient Management
Section titled “Clinical Applications in Patient Management”The measurement of LDL cholesterol is a routine and critical component of cardiovascular risk assessment, serving as a key diagnostic and monitoring biomarker in clinical care.[3] Integrating genetic risk profiles into clinical practice can enhance personalized medicine approaches by identifying high-risk individuals more accurately, thereby informing targeted prevention strategies and earlier interventions. [11] While LDL-lowering therapies are well-established, the identification of specific genetic loci that influence lipid concentrations, such as those found in GWAS, nominates these regions as high-priority targets for further investigation into novel pharmacological interventions. [5]Such genetic information could potentially guide treatment selection and optimize monitoring strategies, leading to improved long-term patient outcomes in the management of dyslipidemia and associated cardiovascular complications.[11]
References
Section titled “References”[1] 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. 1824-30.
[2] Sabatti, C et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 41, no. 1, 2009, pp. 35-46. PMID: 19060910.
[3] 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.
[4] 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. 189-97.
[5] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.
[6] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.” Nat Genet 40.2 (2008): 161-169.
[7] Kuivenhoven, JA. et al. “The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.” J Lipid Res, vol. 38, no. 2, 1997, pp. 191–205.
[8] Pollin, T. I. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science 322.5906 (2008): 1090-1093.
[9] Maxwell, KN., Fisher, EA., and Breslow, JL. “Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.” Proc. Natl. Acad. Sci. USA, vol. 102, 2005, pp. 2069–2074.
[10] Cohen, JC. et al. “Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.”N. Engl. J. Med., vol. 354, 2006, pp. 1264–1272.
[11] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.” Nat Genet 40.2 (2008): 198-208.