Free Cholesterol In Small Hdl
Background
Section titled “Background”High-density lipoprotein (HDL), often referred to as “good cholesterol,” plays a critical role in lipid metabolism by facilitating the transport of cholesterol from peripheral tissues back to the liver for excretion, a process known as reverse cholesterol transport. Cholesterol within HDL particles can exist in both esterified and unesterified (free) forms. HDL particles are heterogeneous and can be categorized into various subfractions based on size and density, with smaller HDL particles representing a distinct component of this complex system. Understanding the composition and function of these specific subfractions, such as free cholesterol in small HDL, is important for a comprehensive view of cholesterol dynamics.
Biological Basis
Section titled “Biological Basis”The levels of HDL cholesterol and its subfractions are influenced by a complex interplay of genetic and environmental factors. Numerous genes have been identified through genome-wide association studies (GWAS) that contribute to the variability in HDL cholesterol concentrations. For example, common single nucleotide polymorphisms (SNPs) in genes likeGALNT2 (rs4846914 ) have been associated with lower HDL concentrations, while others, such as rs17145738 near TBL2 and MLXIPL, are linked to higher HDL concentrations. [1] An SNP (rs17321515 ) near TRIB1 is also associated with higher HDL cholesterol. [1]
Other established loci influencing HDL cholesterol include ABCA1, APOA1-APOC3-APOA4-APOA5, CETP, LIPC, LIPG, and LPL. [1] Studies indicate that common SNPs can act in concert to affect plasma levels of HDL cholesterol. [2] A specific polymorphism in HNF4A(G319S variant) has also been associated with plasma lipoprotein variation.[3] Furthermore, increased prebeta-HDL, apolipoprotein AI, and phospholipid have been observed in mice expressing human phospholipid transfer protein and human apolipoprotein AI transgenes. [4]These genetic insights highlight the intricate molecular pathways governing HDL metabolism, including the handling of free cholesterol within its various subparticles.
Clinical Relevance
Section titled “Clinical Relevance”Maintaining healthy cholesterol levels, including HDL cholesterol, is clinically relevant due to its strong association with cardiovascular disease (CVD) risk. Low levels of HDL cholesterol are a well-established risk factor for coronary heart disease.[5]Genetic variations that influence HDL levels contribute to polygenic dyslipidemia, a condition characterized by abnormal lipid profiles that increases the risk of heart disease.[1]The National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines emphasize the importance of monitoring and managing blood cholesterol levels, including HDL, to reduce cardiovascular risk.[6]Understanding the genetic determinants of specific HDL components, such as free cholesterol in small HDL, could offer more refined markers for cardiovascular risk assessment and potentially guide targeted therapeutic strategies.
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide.[7]Research into the genetic underpinnings of lipid metabolism, including factors like free cholesterol in small HDL, has significant social importance. It contributes to a deeper understanding of disease pathogenesis, enabling improved risk prediction and the development of personalized prevention and treatment strategies. Genetic studies conducted across diverse populations, such as those involving Micronesians and Caucasians, underscore the global impact of these findings and the need for inclusive research to address health disparities.[8]By elucidating the genetic architecture of lipid traits, this research aims to mitigate the societal burden of cardiovascular disease.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The studies primarily employed an additive model of inheritance for genotype-phenotype association analyses, which might not fully capture complex genetic architectures involving dominant, recessive, or epistatic interactions. [1] While large sample sizes were achieved through meta-analyses of multiple genome-wide association studies (GWAS), the overall power for discovering all genetic variants contributing to complex traits like HDL cholesterol remains a challenge, suggesting that further loci with smaller effect sizes may still be unidentified. [9] Furthermore, the exclusion of individuals on lipid-lowering therapy from most analyses means that the findings are primarily generalizable to untreated populations, potentially limiting the direct applicability of these genetic associations in clinical settings where such therapies are common. [1]
Specific methodological variances across cohorts could also introduce subtle biases or affect the consistency of findings. For instance, in some studies, age2 was not considered as an adjustment variable, and outlier individuals in the lipid distributions were excluded, while in others, information on lipid-lowering therapy was unavailable and thus not accounted for. [1] These inconsistencies in phenotype adjustment and data handling, alongside instances where replication efforts for certain loci yielded only borderline significance, highlight the need for standardized protocols and continued rigorous validation across diverse datasets. [10]Such variations can impact the precision of effect size estimates and the overall robustness of genetic associations identified.
Generalizability and Phenotypic Nuances
Section titled “Generalizability and Phenotypic Nuances”A significant limitation stems from the demographic composition of the study cohorts, which were predominantly of European ancestry. [1] While attempts were made to extend findings to multiethnic samples, the primary discovery and replication efforts largely excluded individuals of non-European descent, limiting the generalizability of these genetic associations to diverse global populations. [1] Differences in linkage disequilibrium patterns and allele frequencies across ancestries mean that variants identified in one population may not have the same effect or even exist in others, necessitating further research in ethnically diverse cohorts. [8]
The definition and measurement of lipid phenotypes also present nuances. The analyses often relied on multivariable-adjusted residual lipid concentrations, which are derived after accounting for factors like age, gender, and diabetes status. [1]While this approach helps isolate genetic effects, it means the reported associations are with an adjusted, rather than raw, phenotypic value, which might not fully reflect the complex biological interplay in vivo. Additionally, some studies used specific methodologies for calculating lipid levels, such as the Friedewald formula for LDL cholesterol, which has known limitations, particularly with elevated triglyceride levels.[9] Such methodological specificities can influence the accuracy and comparability of lipid measurements across different studies.
Remaining Heritability and Unaccounted Influences
Section titled “Remaining Heritability and Unaccounted Influences”Despite the identification of numerous genetic loci, the collective contribution of these variants explains only a modest proportion of the total variance in HDL cholesterol concentrations, with figures around 9.3% reported for HDL cholesterol. [9] This substantial “missing heritability” indicates that a large fraction of the genetic and non-genetic factors influencing HDL cholesterol remains undiscovered. The unexplained variance points to the existence of many more common variants with smaller effects, rare variants, structural variations, or complex gene-gene and gene-environment interactions yet to be elucidated.
Furthermore, the studies, while adjusting for basic demographic and health factors, may not have comprehensively accounted for all potential environmental or gene-environment confounders. Factors such as specific dietary patterns, physical activity levels, smoking status, or the use of various medications (beyond lipid-lowering therapies) were not consistently or fully integrated into the adjustment models across all cohorts.[1]The interplay between genetic predispositions and these environmental factors is crucial for a complete understanding of lipid metabolism, and their omission or incomplete consideration represents a knowledge gap in fully characterizing the etiology of free cholesterol in small HDL levels.
Variants
Section titled “Variants”Variants across several genes play a significant role in modulating lipid metabolism, particularly influencing the levels of free cholesterol within small high-density lipoprotein (HDL) particles. TheAPOE gene, for example, is central to lipid transport and clearance, with its common variant rs7412 being a key determinant of the APOE protein isoforms (e.g., E2, E3, E4). These isoforms affect how efficiently cholesterol-rich lipoproteins, including remnants, are cleared from the bloodstream, thereby influencing overall cholesterol distribution and the availability of cholesterol for transfer to HDL. The LDLRgene encodes the low-density lipoprotein receptor, which is crucial for removing LDL cholesterol from circulation. Variants likers6511720 in LDLR can alter receptor function, impacting LDL levels and indirectly affecting the reverse cholesterol transport pathway, which involves HDL. [11] The GCKRgene, encoding glucokinase regulatory protein, primarily affects glucose metabolism but also has a strong association with triglyceride levels. Thers1260326 variant in GCKRcan lead to altered liver fat and triglyceride synthesis, factors that significantly influence HDL composition and the amount of free cholesterol it carries. Together, these genetic variations contribute to a complex interplay that determines an individual’s lipid profile and the characteristics of their small HDL.
The CETP(Cholesteryl Ester Transfer Protein) gene andLIPG(Endothelial Lipase) gene are directly involved in the remodeling of HDL particles, profoundly affecting their size and cholesterol content.CETPfacilitates the exchange of cholesteryl esters from HDL to triglyceride-rich lipoproteins in exchange for triglycerides, a process that can reduce HDL cholesterol levels. Variants such asrs3816117 and rs289714 in CETPare known to modify its activity, thereby influencing HDL particle size and the amount of free cholesterol available in small HDL. Similarly,LIPGencodes an endothelial lipase that hydrolyzes phospholipids and triglycerides in HDL, contributing to its maturation and catabolism. Genetic variations likers9304381 (near LIPG - SMUG1P1) and rs77960347 in LIPGcan alter enzyme activity, leading to changes in HDL particle size distribution and free cholesterol content, particularly affecting smaller, denser HDL particles. Understanding these variants helps explain individual differences in HDL metabolism and cardiovascular risk.
Further contributing to the intricate regulation of lipid profiles are genes such as PLTP, APOC3 - APOA1, and TRIB1AL. The PLTP gene, encoding phospholipid transfer protein, plays a vital role in transferring phospholipids and cholesterol between lipoproteins, influencing HDL remodeling and stability. Variants like rs6073958 and rs139953093 in PLTPcan impact its activity, altering the composition and functionality of HDL, including its free cholesterol content. TheAPOC3 and APOA1genes are located in a cluster crucial for lipoprotein metabolism;APOA1 is the main structural protein of HDL, while APOC3inhibits triglyceride clearance. Thers525028 variant in the intergenic region between APOC3 and APOA1can influence the expression of these genes, thereby affecting triglyceride levels, HDL particle number, and the amount of free cholesterol in small HDL. Additionally, theTRIB1AL gene (likely referring to TRIB1) is involved in regulating triglyceride metabolism by influencing VLDL assembly and secretion, with variantrs112875651 potentially impacting these pathways and indirectly affecting HDL composition.
Finally, variants in ALDH1A2, such as rs261290 and rs35853021 , contribute to the broader metabolic context influencing lipid homeostasis. ALDH1A2encodes an aldehyde dehydrogenase involved in retinoic acid synthesis, a signaling molecule with diverse metabolic functions. While less directly associated with core lipid transfer processes, variations in this gene can affect metabolic pathways that indirectly modulate systemic inflammation, insulin sensitivity, and liver lipid metabolism. These broader metabolic effects can, in turn, influence the overall lipid environment, including the generation and remodeling of small HDL particles and their free cholesterol content. This illustrates how genetic variations with seemingly distant primary functions can still contribute to the complex regulation of lipoprotein profiles.
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Definition and Biological Significance of HDL Cholesterol
Section titled “Definition and Biological Significance of HDL Cholesterol”High-density lipoprotein (HDL) cholesterol is a crucial lipid trait and biomarker in human health, widely recognized for its inverse association with cardiovascular disease risk.[12]Often referred to in general terms as “HDL” or “HDL cholesterol,” this lipoprotein class plays a significant role in lipid metabolism. Research indicates that even a modest increase in HDL cholesterol concentrations, such as a 1% rise, is associated with an approximate 2% reduction in the risk of coronary heart disease.[9]This highlights its importance as a protective factor against atherosclerotic processes and subsequent cardiovascular events.
Measurement and Operational Definitions
Section titled “Measurement and Operational Definitions”The quantification of HDL cholesterol typically involves standardized laboratory procedures using fasting blood samples [1]. [11] For accurate assessment, individuals are generally instructed to fast for a specified duration, with examples including at least 4 hours, or often overnight, before blood collection [1]. [11] Concentrations are commonly determined using enzymatic methods [1]. [11] In research and clinical contexts, measured HDL cholesterol values are frequently adjusted for covariates such as age, age squared, gender, diabetes status, and enrolling center to account for potential confounding factors in genotype-phenotype association analyses [1]. [13]
Clinical Classification and Risk Stratification
Section titled “Clinical Classification and Risk Stratification”HDL cholesterol levels are a key factor in the classification of an individual’s cardiovascular risk profile. Specifically, low levels of HDL cholesterol are well-established as an independent risk factor for coronary heart disease.[5] While specific diagnostic thresholds for “low” levels are not detailed in all contexts, the consistent recognition of this association underscores its importance in clinical assessment and patient management. Individuals undergoing lipid-lowering therapy or those with diabetes are often excluded from studies analyzing untreated lipid traits to ensure the purity of the observed associations [1]. [11]This categorical classification helps guide therapeutic interventions aimed at mitigating cardiovascular risk.
The provided research context does not contain specific information regarding the causes of ‘free cholesterol in small HDL’. The studies primarily discuss general high-density lipoprotein cholesterol (HDL cholesterol) levels, low-density lipoprotein cholesterol (LDL cholesterol) levels, and triglycerides, along with genetic loci associated with these broader lipid phenotypes. Information distinguishing between different HDL subfractions (e.g., small HDL vs. large HDL) or the specific component of free cholesterol within these particles is not detailed.
Biological Background
Section titled “Biological Background”Cholesterol Metabolism and Cellular Homeostasis
Section titled “Cholesterol Metabolism and Cellular Homeostasis”Cellular cholesterol homeostasis is a tightly regulated process essential for maintaining cell membrane integrity and serving as a precursor for steroid hormones and bile acids. A central enzyme in the endogenous synthesis of cholesterol is 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a rate-limiting step in the mevalonate pathway. [8] The activity of HMGCR is subject to complex regulatory mechanisms, including transcriptional and post-transcriptional controls, and notably, alternative splicing. [8] When HMGCRactivity decreases, cellular cholesterol synthesis is reduced, prompting a compensatory increase in cholesterol uptake from the plasma through the low-density lipoprotein (LDL) receptor pathway to preserve intracellular cholesterol balance.[8]
Another crucial protein influencing cholesterol levels is Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), which plays a significant role in regulating the degradation of the LDL receptor. [14] By accelerating the breakdown of LDL receptors, PCSK9 reduces the liver’s capacity to clear LDL cholesterol from the bloodstream, thereby increasing circulating LDL cholesterol levels. [14] Conversely, genetic variations leading to reduced PCSK9function are associated with lower LDL cholesterol and protection against coronary heart disease.[15] These interconnected molecular and cellular pathways highlight the intricate network governing cholesterol levels within the body.
High-Density Lipoprotein (HDL) Function and Dynamics
Section titled “High-Density Lipoprotein (HDL) Function and Dynamics”High-density lipoprotein (HDL) particles are integral to reverse cholesterol transport, a process where excess cholesterol is removed from peripheral cells and transported back to the liver for excretion.[16]This function is critical for cardiovascular health, as high concentrations of HDL cholesterol are consistently associated with a decreased risk of coronary artery disease (CAD).[9]Apolipoprotein C-III (APOC3) is a key biomolecule found on both HDL and apoB-containing lipoprotein particles, secreted primarily by the liver and to a lesser extent by the intestines.[16]
APOC3 plays a complex role in lipid metabolism, as it impairs the catabolism and hepatic uptake of apoB-containing lipoproteins and appears to enhance the catabolism of HDL. [16] A null mutation in human APOC3has been shown to result in a favorable plasma lipid profile, characterized by lower triglyceride and LDL cholesterol levels, and is associated with apparent cardioprotection.[16]This demonstrates how specific proteins embedded within HDL particles modulate their metabolism and overall impact on circulating lipid levels and disease risk.
Genetic Modulators of Lipid Profiles
Section titled “Genetic Modulators of Lipid Profiles”Plasma lipid levels, including HDL cholesterol, are complex genetic traits influenced by numerous genetic variations across the human genome. [1]Common single nucleotide polymorphisms (SNPs) in theHMGCR gene, for instance, are associated with LDL cholesterol levels and impact the alternative splicing of exon 13. [8] Specifically, alleles associated with lower LDL cholesterol levels correlate with higher levels of an alternatively spliced HMGCR mRNA variant lacking exon 13. [8] This suggests that alternative splicing of HMGCR can act as an additional regulatory mechanism, influencing cellular cholesterol synthesis and consequently plasma cholesterol levels. [8]
Beyond HMGCR, genome-wide association studies have identified common variants at multiple other loci that contribute to polygenic dyslipidemia. [1] For example, a common variant at ANGPTL4 is strongly associated with HDL cholesterol levels. [1] While genes like HNF4A and HNF1A are known to affect plasma cholesterol levels in animal models, their association with HDL or LDL cholesterol concentrations in humans has been more modest. [1] These genetic insights underscore the polygenic nature of lipid regulation and provide targets for understanding inherited predispositions to dyslipidemia.
Systemic Lipid Dysregulation and Cardiovascular Risk
Section titled “Systemic Lipid Dysregulation and Cardiovascular Risk”Dyslipidemia, characterized by abnormal concentrations of lipoproteins, is a significant pathophysiological process contributing to major global health burdens such as coronary artery disease (CAD) and stroke.[9]Atherosclerosis, the underlying pathology for these conditions, involves the cumulative deposition of LDL cholesterol in arterial walls, eventually leading to impaired blood flow and events like myocardial infarction or stroke.[9] The balance between LDL cholesterol and HDL cholesterol is critical, with high LDL cholesterol increasing CAD risk and high HDL cholesterol decreasing it. [9]
Each 1% increase in HDL cholesterol concentrations is estimated to reduce the risk of coronary heart disease by approximately 2%.[9] This independent association between HDL cholesterol and CAD risk highlights the importance of maintaining healthy HDL levels. [9]The genetic variations influencing lipid profiles contribute to individual differences in dyslipidemia susceptibility and, consequently, to varying risks of developing cardiovascular diseases.[1] Understanding these systemic consequences is vital for developing strategies to prevent and treat lipid-related disorders.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Regulation of Cholesterol Synthesis and LDL Receptor Activity
Section titled “Regulation of Cholesterol Synthesis and LDL Receptor Activity”The biosynthesis of cholesterol is a tightly regulated metabolic pathway, with 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) serving as a rate-limiting enzyme in the mevalonate pathway. HMGCR’s activity is critical for maintaining cellular cholesterol homeostasis and influencing plasma cholesterol levels. The regulation of this pathway involves complex feedback mechanisms, and genetic variations, such as common single nucleotide polymorphisms inHMGCR, can impact its function by affecting alternative splicing, specifically of exon13, which consequently influences cellular cholesterol levels. Understanding these precise splicing mechanisms is key to comprehending HMGCR’s role in lipid regulation. [8]
Beyond synthesis, the clearance of cholesterol from circulation is primarily mediated by the low-density lipoprotein receptor (LDLR). The availability and activity of LDLR are critically controlled by proprotein convertase subtilisin/kexin type 9 (PCSK9), which acts through a post-transcriptional mechanism. PCSK9 accelerates the degradation of LDLRin a post-endoplasmic reticulum compartment, thereby reducing the number of functional receptors on the cell surface and leading to increased plasma low-density lipoprotein (LDL) cholesterol levels. Genetic variations inPCSK9 can profoundly impact LDLRregulation; certain mutations are known to cause autosomal dominant hypercholesterolemia, while others are associated with lower LDL levels and protection against coronary heart disease.[17]
Dynamics of HDL Metabolism and Lipoprotein Remodeling
Section titled “Dynamics of HDL Metabolism and Lipoprotein Remodeling”High-density lipoprotein (HDL) particles are central to reverse cholesterol transport, facilitating the efflux of cholesterol from peripheral cells back to the liver. Apolipoprotein C-III (APOC3), secreted predominantly by the liver and to a lesser extent by the intestines, is a key component of both HDL and apoB-containing lipoprotein particles.APOC3 functions by impairing the catabolism and hepatic uptake of apoB-containing lipoproteins, while also appearing to enhance the catabolism of HDL itself. Consequently, a null mutation in human APOC3 is associated with a favorable plasma lipid profile and offers apparent cardioprotection, underscoring its significant role in lipid homeostasis. [16]
Another crucial enzyme in HDL metabolism is lecithin-cholesterol acyltransferase (LCAT), which catalyzes the esterification of free cholesterol within HDL particles into cholesteryl esters. This process is essential for the maturation of nascent HDL, including small HDL particles, and enhances their capacity to accept free cholesterol from cells. Defects inLCAT, such as specific amino acid exchanges, can lead to conditions like fish eye disease, characterized by the selective loss of alpha-LCAT activity and significant dyslipidemia, highlighting LCAT’s irreplaceable function in maintaining HDL structure and cholesterol efflux capacity. The presence of apolipoprotein A-I (APOA1), a major structural protein of HDL, along with human phospholipid transfer protein, can also lead to increased prebeta-high density lipoprotein and phospholipids, further impacting HDL remodeling and the dynamics of free cholesterol.[18]
Transcriptional and Post-Transcriptional Gene Regulation
Section titled “Transcriptional and Post-Transcriptional Gene Regulation”The intricate regulation of lipid metabolism is orchestrated by a hierarchical network of transcription factors that control gene expression. Hepatocyte nuclear factor 4 alpha (HNF4A) is a pivotal nuclear receptor essential for maintaining hepatic gene expression and overall lipid homeostasis. Similarly, hepatocyte nuclear factor 1 alpha (HNF1A) plays an essential role in regulating bile acid and plasma cholesterol metabolism, illustrating how these transcription factors orchestrate broad metabolic processes. Dysregulation in these factors can lead to altered lipid profiles and contribute to disease states such as type 2 diabetes.[19]
Beyond transcriptional control, post-transcriptional mechanisms, particularly alternative splicing, significantly modulate protein diversity and function, with direct implications for lipid metabolism. For example, common single nucleotide polymorphisms inHMGCR can lead to alternative splicing of exon13, directly influencing the enzyme’s activity and consequently cellular cholesterol levels. Another notable instance is the APOBtranscript, where exon27 skipping can specifically reduce the amount of functional ApoB100 protein while preserving ApoB48 levels, thereby altering lipoprotein composition and metabolism. These precise splicing events demonstrate a sophisticated layer of gene regulation critical for fine-tuning lipid pathways.[8]
Systems-Level Integration and Disease Mechanisms
Section titled “Systems-Level Integration and Disease Mechanisms”Lipid metabolism is not an isolated process but rather a highly integrated system where multiple pathways interact and influence emergent properties of the overall lipid profile. Genetic variations across different loci collectively contribute to polygenic dyslipidemia, influencing plasma levels of various lipids, including HDL cholesterol. For instance, common single nucleotide polymorphisms in theFADS1/FADS2 gene cluster are associated with the fatty acid composition in phospholipids, and dietary omega-3 polyunsaturated fatty acids, a key substrate for FADS1, are known to lower plasma triglycerides, illustrating a direct link between genetic predisposition, dietary factors, and metabolic flux. [20]
Furthermore, genes like TTC39B, whose exact function in humans is still being elucidated but is generally understood to be involved in protein-protein interactions, have been associated with HDL cholesterol levels, where lower transcript levels correlate with higher HDL cholesterol. The hepatic cholesterol transporter ABCG8has also been identified as a susceptibility factor for human gallstone disease, showcasing how specific genetic components contribute to broader metabolic disorders. Understanding these complex network interactions, pathway crosstalk, and hierarchical regulation is crucial for identifying therapeutic targets and developing strategies to address pathway dysregulation and compensatory mechanisms in lipid-related diseases.[1]
References
Section titled “References”[1] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 12, 2008, pp. 1414-1422.
[2] Spirin, V., et al. “Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol.”Am. J. Hum. Genet., vol. 81, no. 6, 2007, pp. 1298–1303.
[3] 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, 2000, pp. 217–222.
[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 Clin Invest, vol. 90, 1992, pp. 1889–1900.
[5] Gotto, A. M. Jr., and E. A. Brinton. “Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update.”Journal of the American College of Cardiology, 2004.
[6] Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, vol. 285, no. 19, 2001, pp. 2486–2497.
[7] Mackay, Judith, and George A. Mensah. The Atlas of Heart Disease and Stroke. World Health Organization, 2004.
[8] 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. 11, 2008, pp. 2078-2085.
[9] 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.
[10] Wallace, Cathryn, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”The American Journal of Human Genetics, vol. 82, no. 1, 2008, pp. 139-149.
[11] Sabatti, C., et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nature Genetics, 2009.
[12] Benjamin, E. J. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, 2007.
[13] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nature Genetics, 2009.
[14] Maxwell, K. N., Fisher, E. A., & Breslow, J. L. “Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.” Proc. Natl. Acad. Sci. USA, vol. 102, no. 6, 2005, pp. 2069-2074.
[15] Cohen, J., et al. “Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.” Nat. Genet., vol. 37, no. 2, 2005, pp. 161-165.
[16] 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. 1092-1095.
[17] Park, S. W., Moon, Y. A., & Horton, J. D. “Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.”J. Biol. Chem., vol. 279, no. 48, 2004, pp. 50630-50638.
[18] Frohlich, J., et al. “A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.”Proc Natl Acad Sci U S A, vol. 88, no. 11, 1991, pp. 4855-4859.
[19] Hayhurst, G.P., et al. “Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.” Mol Cell Biol, vol. 21, no. 4, 2001, pp. 1393-1403.
[20] Schaeffer, L., et al. “Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.” Hum Mol Genet, vol. 15, no. 11, 2006, pp. 1745-1756.