Apolipoprotein C

Background

Apolipoproteins are proteins that play a vital role in the transport of fats, such as triglycerides and cholesterol, through the bloodstream. They bind to lipids to form lipoproteins, which are essential for the absorption and distribution of dietary fats and cholesterol throughout the body. Apolipoprotein C refers to a family of small apolipoproteins, includingAPOC1, APOC2, APOC3, and APOC4, which are found on the surface of various lipoprotein particles. Among these, apolipoprotein C-III (APOC3) is particularly significant due to its well-established role in lipid metabolism and its strong association with metabolic health and disease.

Biological Basis

Apolipoprotein C-III (APOC3) is a key regulator of triglyceride metabolism. It is primarily synthesized in the liver^[1]and plays a crucial role by inhibiting lipoprotein lipase (LPL) activity. Lipoprotein lipase is an enzyme responsible for hydrolyzing triglycerides in very-low-density lipoproteins (VLDL) and chylomicrons, facilitating their uptake by tissues. By inhibiting LPL,APOC3reduces the efficient clearance of triglyceride-rich lipoproteins from the bloodstream, leading to higher plasma triglyceride levels. It also interferes with the liver’s ability to take up remnant lipoproteins.

Clinical Relevance

Genetic variations within the APOC3 gene can have a profound impact on an individual’s plasma lipid profile. For example, a null mutation, such as R19X, in the APOC3 gene leads to significantly reduced levels of functional APOC3 protein. ^[2]Individuals who carry such mutations often exhibit a favorable lipid profile characterized by notably decreased fasting triglyceride levels and increased high-density lipoprotein cholesterol (HDL-C) levels.^[2]These beneficial changes in lipid parameters are also associated with lower low-density lipoprotein cholesterol (LDL-C) levels. Such a lipid profile is considered cardioprotective and is linked to a reduced risk of coronary artery disease.^[2] Furthermore, the APOE/APOC gene cluster, which encompasses APOC3, has been identified as a region influencing LDL cholesterol concentrations. ^[3]

Social Importance

The study of apolipoprotein C, particularlyAPOC3, holds considerable social importance due to its direct link to cardiovascular health. Elevated triglyceride levels are a recognized risk factor for cardiovascular diseases, which are a major global health burden. Research intoAPOC3 helps to elucidate the genetic underpinnings of dyslipidemia and provides insights into natural mechanisms that can protect against adverse lipid profiles. Identifying genetic variants that confer improved lipid profiles, such as the null mutations in APOC3, can guide the development of novel therapeutic strategies for managing hypertriglyceridemia and preventing heart disease. This understanding contributes to the advancement of personalized medicine, allowing for more targeted interventions and tailored recommendations for maintaining cardiovascular well-being.

Limitations

Research into the genetic influences on apolipoprotein C, particularly within the larger context of lipid metabolism, faces several inherent limitations related to study design, generalizability, and the complexity of biological systems. These factors necessitate careful interpretation of findings and highlight areas for future investigation.

Methodological and Statistical Constraints

Many studies are constrained by sample sizes, which can limit the power to detect genetic associations with modest effect sizes, potentially leading to false negative findings. ^[4] Conversely, the extensive multiple testing inherent in genome-wide association studies (GWAS) increases the risk of identifying false positive associations, even for moderately strong statistical signals. ^[4] The need for replication in independent cohorts is frequently emphasized as a crucial step for validating initial discoveries. ^[4] Furthermore, the reliance on imputation to infer missing genotypes, while a standard practice, introduces an estimated error rate in genotype calls, impacting the precision of association analyses. ^[3]

Generalizability and Phenotype Assessment

The generalizability of findings is often restricted by the demographic characteristics of study populations, which are frequently composed predominantly of individuals of European ancestry. ^[5] This limits the applicability of results to diverse global populations and may obscure ancestry-specific genetic effects. Furthermore, studies often exclude individuals on lipid-lowering therapies, which, while necessary to assess baseline genetic effects, reduces the ability to generalize findings to the broader population where such medications are common. ^[1] Phenotype assessment itself can be challenging; for instance, averaging biomarker levels over time, while potentially reducing measurement error, might also incorporate “noisy” measures if participants’ physiological states (e.g., statin exposure or acute-phase responses) vary significantly during the observation period. ^[6]

Unaccounted Genetic and Environmental Factors

A significant challenge lies in accounting for the complex interplay between genetic variants and environmental factors. Many studies do not undertake comprehensive investigations into gene-environment interactions, despite evidence that environmental influences, such as diet, can modulate genetic associations with phenotypes.^[7]This omission contributes to the “missing heritability” problem, where the identified genetic variants explain only a small fraction of the total phenotypic variability for traits like apolipoprotein C.^[8]Therefore, a substantial portion of the genetic and environmental influences on apolipoprotein C levels remains to be fully elucidated, highlighting the need for more integrative research designs that consider a wider array of confounding factors.

Variants

Genetic variations play a crucial role in determining an individual’s lipid profile and risk for cardiovascular diseases, often through their influence on apolipoprotein C and related pathways. The apolipoprotein C family, includingAPOC1, APOC2, APOC3, and APOC4, are key components of lipoproteins, regulating their metabolism, synthesis, and catabolism. Variants within or near genes involved in lipoprotein processing can significantly alter circulating lipid levels, such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, as well as triglycerides.

For instance, variants in the GALNT2 gene, such as rs4846913 , rs35498929 , and rs3213497 , are associated with HDL cholesterol concentrations. ^[3] GALNT2 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2) encodes an enzyme involved in O-glycosylation, a post-translational modification essential for the proper function and stability of many proteins, including those involved in lipid metabolism. Alterations in GALNT2activity due to these variants can affect the glycosylation of apolipoproteins or lipid-processing enzymes, thereby influencing HDL cholesterol levels and potentially impacting the overall balance of apolipoprotein C-containing lipoproteins. Similarly, theAPOC1 gene, located within a critical cluster alongside APOE, APOC2, and APOC4, is central to lipid metabolism. The variant rs3826688 within APOC1 or its regulatory regions can modulate the gene’s expression or protein function. The APOE-APOC1-APOC4-APOC2 cluster is strongly associated with LDL cholesterol levels, and variants in this region can lead to significant increases in LDL cholesterol. ^[3] APOC1itself is a component of very low-density lipoprotein (VLDL) and HDL, inhibiting hepatic lipase and affecting lipoprotein receptor binding, thus influencing triglyceride and cholesterol clearance.

Other genes, while not as directly linked to apolipoprotein C in the provided studies, contribute to broader metabolic or cellular processes that can indirectly affect lipid homeostasis. TheSLC22A23 gene, with its variant rs9378785 , belongs to the solute carrier family, whose members are typically involved in transporting various molecules across cell membranes. While specific roles for SLC22A23 in lipid metabolism are still under investigation, transporters can influence the cellular uptake or efflux of metabolites, potentially impacting substrate availability for lipid synthesis or breakdown pathways. The FLT3 gene, associated with rs2481968 , encodes a receptor tyrosine kinase primarily known for its role in hematopoietic cell growth and differentiation. However, chronic inflammation or altered immune cell function, which can be influenced by FLT3signaling, are known to perturb lipid metabolism and can affect apolipoprotein C levels indirectly through systemic effects on liver function or lipoprotein remodeling.

Further variants like rs10412211 in CACNA1A, rs2493926 in SASH1, and rs67086575 in IFT172 are linked to genes with diverse cellular functions. CACNA1A encodes a subunit of a voltage-gated calcium channel, critical for neuronal signaling, and dysregulation of calcium homeostasis can have widespread effects on cellular processes, including metabolic regulation. SASH1 is a tumor suppressor gene involved in cell growth and apoptosis, and its disruption could influence cellular stress responses or tissue remodeling that, in turn, might impact metabolic functions. IFT172is involved in intraflagellar transport, crucial for cilia formation and function, and ciliopathies are known to manifest with various metabolic disturbances. While direct connections to apolipoprotein C are not explicitly defined for these genes, their roles in fundamental cellular pathways suggest potential indirect influences on lipid metabolism and overall cardiovascular health.

Finally, variants in non-coding regions, such as rs7175584 within the RN7SKP181 - LINC02253 locus and rs9462715 within the SUMO2P12 - RN7SKP293 locus, represent areas with potential regulatory impact. LINC02253 is a long intergenic non-coding RNA, and pseudogenes like RN7SKP181, SUMO2P12, and RN7SKP293can sometimes play regulatory roles by influencing the expression of protein-coding genes or by acting as competitive endogenous RNAs. Variations in these regions could affect the transcription, stability, or translation of nearby or distant genes involved in lipid metabolism, thereby indirectly modulating the production or activity of apolipoprotein C and its associated lipoproteins.

Key Variants

RS ID	Gene	Related Traits
rs4846913 rs35498929	GALNT2	depressive symptom measurement, non-high density lipoprotein cholesterol measurement social deprivation, triglyceride measurement blood protein amount triglyceride measurement high density lipoprotein cholesterol measurement
rs9378785	SLC22A23	apolipoprotein c measurement
rs3213497	GALNT2	apolipoprotein c measurement
rs3826688	APOC1	alkaline phosphatase measurement level of vitelline membrane outer layer protein 1 in blood lipid measurement apolipoprotein c measurement memory performance
rs7175584	RN7SKP181 - LINC02253	apolipoprotein c measurement
rs2481968	RN7SL272P - FLT3	apolipoprotein c measurement
rs10412211	CACNA1A	apolipoprotein c measurement
rs2493926	SASH1	apolipoprotein c measurement
rs67086575	IFT172	complex trait apolipoprotein c measurement
rs9462715	SUMO2P12 - RN7SKP293	apolipoprotein c measurement

Classification, Definition, and Terminology

Definition and Metabolic Function

Apolipoprotein C-III (APOC-III) is an apolipoprotein with a specific and significant role in lipid metabolism. It is precisely defined as an inhibitor of triglyceride catabolism, meaning it actively hinders the breakdown of triglycerides within the body.^[1]This inhibitory function is critical for regulating plasma triglyceride levels and is part of the broader conceptual framework of lipoprotein metabolism.APOC-III is synthesized in the liver, underscoring its systemic importance in lipid homeostasis. ^[1]

Genetic Regulation of Apolipoprotein C-III Concentrations

Plasma concentrations of APOC-III are influenced by genetic factors, which can impact an individual’s lipid profile. A notable example is the association with the GCKRP446L allele, corresponding to the single nucleotide polymorphismrs1260326 . ^[1] This specific genetic variant has been identified as contributing to increased concentrations of APOC-III, highlighting a genetic pathway that modulates its levels in the circulation. ^[1]Understanding these genetic determinants aids in classifying individuals based on their predisposition to alteredAPOC-III levels.

Quantitative Assessment and Biomarker Potential

Assessment approaches for APOC-III involve quantifying its plasma concentrations, which serve as a biomarker for evaluating aspects of lipid metabolism. The impact of specific genetic variations, such as the GCKR P446L allele, on APOC-III levels has been quantitatively defined. ^[1] Research indicates that each copy of the minor Leu allele for rs1260326 is associated with a 0.20 standard deviation unit increase in APOC-III concentrations, providing a precise metric for its genetic influence. ^[1] These quantitative associations are crucial for research criteria and potentially for developing thresholds to identify individuals with genetically predisposed higher APOC-III levels.

Signs and Symptoms

Altered Lipid Metabolism and Associated Phenotypes

Apolipoprotein C (specificallyAPOC-III) plays a crucial role in lipid metabolism, primarily acting as an inhibitor of triglyceride catabolism. Elevated concentrations ofAPOC-IIIare directly associated with dyslipidemia, particularly increased triglyceride levels in the blood.^[1] This metabolic alteration contributes to a clinical phenotype characterized by an unfavorable lipid profile, which is a significant component of polygenic dyslipidemia. The severity of this presentation can be quantitatively assessed, with specific genetic variants contributing to measurable increases in APOC-III concentrations and, consequently, altered lipid parameters.

Assessment Methods and Genetic Influences

The assessment of APOC-III involves objective measurement of its plasma concentrations, often as part of a comprehensive lipid panel. Diagnostic tools such as nuclear magnetic resonance (NMR) are employed to quantify various apolipoproteins, including APOC-III, alongside low-, high-, intermediate-, and very low-density lipoprotein particle concentrations.^[1] Inter-individual variability in APOC-III levels can be significantly influenced by genetic factors; for instance, the GCKR P446L allele (rs1260326 ) has been associated with a 0.20 standard deviation unit increase in APOC-III concentration per Leu allele. ^[1] This genetic predisposition highlights a key aspect of phenotypic diversity in lipid metabolism.

Clinical Significance and Prognostic Indicators

The diagnostic significance of APOC-IIIlevels lies in their strong correlation with triglyceride metabolism and overall lipid health. ElevatedAPOC-III concentrations, especially when linked to genetic variants, serve as important biomarkers for identifying individuals at risk for dyslipidemia and its related complications. Understanding these levels can aid in differential diagnosis of various forms of hypertriglyceridemia and contribute to prognostic assessments for metabolic conditions. The role of APOC-IIIas an inhibitor of triglyceride catabolism provides a mechanistic hypothesis for its clinical correlations with metabolic pathways.^[1]

Diagnosis

Genetic and Biochemical Assessment

The diagnosis related to apolipoprotein C, particularlyAPOC-III, involves both biochemical assays to quantify its plasma levels and genetic testing to identify underlying variants influencing its expression or function. Plasma concentrations of APOC-III can be directly measured, as variations in these levels are known to impact lipid metabolism. ^[1] Genetic analysis can identify specific polymorphisms, such as the GCKR P446L allele (rs1260326 ), which is associated with increased concentrations of APOC-III. ^[1] Furthermore, the presence of a null mutation, such as APOC3 R19X, in the human APOC3 gene is a critical diagnostic marker, as it directly correlates with favorable plasma lipid profiles and apparent cardioprotection. ^[2]

Clinical Lipid Profiling and Interpretation

Clinical assessment of apolipoprotein C’s impact relies heavily on standard lipid panel measurements, which reflect its role in triglyceride metabolism. Individuals carrying beneficial genetic variants, such as theAPOC3R19X null mutation, typically exhibit significantly decreased fasting triglycerides (FTG) and increased high-density lipoprotein cholesterol (HDL-C) levels.^[2]These carriers also tend to have lower low-density lipoprotein cholesterol (LDL-C) levels, contributing to an overall favorable lipid profile.^[2]The clinical utility of these findings is substantial, as these lipid parameters are key indicators for cardiovascular disease risk, with optimal LDL-C and cardioprotective HDL-C levels aligning with established clinical guidelines.^[2]

Implications for Dyslipidemia Management

Understanding the genetic and biochemical basis of apolipoprotein C variations is crucial for distinguishing specific patterns of dyslipidemia and guiding management strategies. The presence of a null mutation inAPOC3, for instance, confers a plasma lipid profile characterized by significantly lower fasting triglycerides and higher HDL-C, indicating a reduced risk of coronary heart disease.^[2]This distinct lipid signature can help differentiate individuals with genetically favorable lipid metabolism from those with other forms of dyslipidemia, where elevated triglycerides and lower HDL-C might necessitate different therapeutic interventions. Such diagnostic insights allow for personalized risk assessment and potentially tailored preventive or treatment approaches based on the individual’s apolipoprotein C status.^[2]

Biological Background of Apolipoprotein C-III

Apolipoprotein C-III (apoC-III) is a small protein that plays a central role in lipid metabolism and has significant implications for cardiovascular health. It circulates in the bloodstream primarily associated with triglyceride-rich lipoproteins and high-density lipoprotein (HDL) particles. The biological functions of apoC-III are multifaceted, influencing lipid transport, catabolism, and cellular inflammatory responses.

Role in Lipoprotein Metabolism

Apolipoprotein C-III (apoC-III) is a crucial protein primarily synthesized and secreted by the liver, with a lesser contribution from the intestines. Once secreted, it integrates into both high-density lipoprotein (HDL) particles and apolipoprotein B-containing lipoproteins. Its primary function in lipid metabolism is to inhibit the hydrolysis of triglycerides, thereby influencing the circulating levels of these fat molecules in the bloodstream.^[2]

Beyond its role in triglyceride hydrolysis, apoC-III also plays a significant part in the systemic clearance of lipoproteins. It impairs the normal catabolism and hepatic uptake of apolipoprotein B-containing lipoproteins, which include very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), leading to their prolonged circulation. Furthermore, apoC-III appears to enhance the catabolism of HDL particles, impacting the overall balance of these critical lipid carriers.^[2]

Genetic Regulation and Variation of Apolipoprotein C-III

The production and function of apolipoprotein C-III are directly governed by theAPOC3 gene. Genetic variations within this gene can significantly alter apoC-III levels and, consequently, lipid profiles. For instance, a specific null mutation, R19X, in the APOC3 gene has been identified, where carriers express approximately half the normal amount of apoC-III protein. ^[2]

This genetic variation has profound implications for metabolic health. Studies have shown that individuals carrying the R19X null mutation exhibit a favorable plasma lipid profile, characterized by decreased fasting triglycerides, increased high-density lipoprotein cholesterol (HDL-C), and lower low-density lipoprotein cholesterol (LDL-C). This genetic predisposition to lower apoC-III levels mimics the effects of certain lipid-lowering therapies, as indirect reduction ofAPOC3 expression is a known mechanism for drugs like fibrates, and other agents such as statins, thiazolidinediones, and niacin are also associated with reduced apoC-III. ^[2]

Pathophysiological Impact on Cardiovascular Health

The precise regulation of apolipoprotein C-III levels is critical for maintaining cardiovascular health, as dysregulation can contribute to disease mechanisms. Elevated concentrations of apoC-III have been consistently associated with an increased risk of coronary heart disease (CHD). This link highlights apoC-III as a potential factor in the development and progression of atherosclerotic disease.^[2]

Conversely, a deficiency in apoC-III, such as that caused by the R19X null mutation, appears to confer significant cardioprotection. Individuals with reduced apoC-III levels show a favorable lipid profile and reduced subclinical coronary artery atherosclerosis. Specifically, these carriers are less likely to have high coronary artery calcium (CAC) scores, which are strong predictors of increased coronary event risk, and exhibit higher levels of cardioprotective HDL-C.^[2]

Role in Cellular Inflammation and Atherogenesis

Beyond its direct effects on lipid metabolism, apolipoprotein C-III is also implicated in cellular inflammatory responses, contributing to pathophysiological processes like atherogenesis. It has been observed to enhance the adhesion of monocytes to vascular endothelial cells, a critical early step in the development of atherosclerotic plaques. This cellular interaction promotes the recruitment of immune cells to the arterial wall, fostering an inflammatory environment.^[2]

Furthermore, apoC-III actively activates inflammatory signaling pathways within cells. This activation can exacerbate vascular inflammation, contributing to the overall atherosclerotic tendency. The combined effects of impaired lipoprotein clearance and enhanced inflammatory responses underscore apoC-III’s multifaceted role in cardiovascular disease, suggesting that its deficiency could decrease atherothrombotic risk.^[2]

Pathways and Mechanisms

Metabolic Control of Triglyceride and Lipoprotein Flux

APOC3plays a critical role in the metabolic regulation of triglyceride levels in the plasma. Its primary known function is to inhibit the hydrolysis of triglycerides, a process essential for the efficient clearance of triglyceride-rich lipoproteins (TRLs) from circulation.^[2] By impeding this catabolic pathway, APOC3directly influences the flux of lipids, leading to elevated triglyceride concentrations. Furthermore, it impairs the catabolism and hepatic uptake of apoB-containing lipoproteins, which include very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles, contributing to their prolonged presence in the bloodstream.^[2] In studies involving human apolipoprotein CIII transgenic mice, increased APOC3 has been shown to diminish the fractional catabolic rate of VLDL particles, a mechanism associated with both elevated APOC3 and reduced APOE content on these particles. ^[9] This complex interplay underscores APOC3’s central role in modulating lipid clearance and overall metabolic homeostasis.

Lipoprotein Particle Integration and Inter-Apolipoprotein Dynamics

Apolipoprotein C-III is a dynamic component of various lipoprotein particles, secreted predominantly by the liver and to a lesser extent by the intestines.^[2]It associates with both high-density lipoprotein (HDL) and apoB-containing lipoprotein particles, acting as a crucial mediator of their metabolic fate.^[2]This integration into different lipoprotein classes facilitates its regulatory functions, influencing the systemic distribution and processing of lipids. The presence ofAPOC3 on VLDL particles, for instance, is linked to a reduction in the APOE content on these particles, suggesting a competitive or modulatory interaction that significantly impacts VLDL catabolism. ^[9] This intricate pathway crosstalk between apolipoproteins on shared lipid carriers highlights a systems-level integration where APOC3exerts broad effects on the entire lipoprotein network.

Genetic Regulation of APOC3 Expression and Function

The expression and functional activity of apolipoprotein C-III are subject to genetic regulation, with variations in theAPOC3 gene directly impacting circulating protein levels and downstream metabolic effects. For example, a null mutation, specifically the R19X variant in human APOC3, results in a significant reduction in functional apoC-III protein, with heterozygous carriers expressing approximately half the amount found in non-carriers. ^[2]This genetic alteration demonstrates how gene regulation at the translational level can profoundly alter protein quantity and, consequently, its inhibitory effects on triglyceride hydrolysis and lipoprotein catabolism. Such regulatory mechanisms highlight the importance of genetic determinants in shaping an individual’s lipid profile and overall metabolic health.

APOC3Dysregulation in Cardiometabolic Disease

Dysregulation of APOC3 pathways is critically implicated in the development and progression of cardiometabolic diseases, particularly those characterized by altered lipid profiles. The presence of a null mutation in APOC3, which leads to reduced apoC-III levels, confers a favorable plasma lipid profile characterized by lower triglycerides and is associated with apparent cardioprotection. ^[2]This beneficial outcome arises from the diminished inhibitory effect of apoC-III on triglyceride hydrolysis and lipoprotein clearance. Conversely, elevatedAPOC3levels contribute to hypertriglyceridemia and are implicated in coronary artery disease, establishingAPOC3as a key therapeutic target for managing dyslipidemia and reducing cardiovascular risk.^[2]These observations underscore how specific pathway dysregulations can lead to emergent properties at the systems level, influencing disease susceptibility and progression.

Clinical Relevance of Apolipoprotein C-III

Role in Lipid Metabolism and Cardiovascular Risk

Apolipoprotein C-III (APOC3) is a key regulator of lipid metabolism, primarily functioning as an inhibitor of lipoprotein lipase, an enzyme essential for the breakdown of triglycerides.^[2] Consequently, elevated APOC3levels are directly associated with increased plasma triglyceride concentrations and have been implicated in the development and progression of coronary artery disease (CAD).^[2]Understanding this inhibitory role is crucial for comprehending dyslipidemia phenotypes, where high triglyceride levels contribute significantly to cardiovascular risk. Genetic studies further highlight this relationship, with theGCKR P446L allele (rs1260326 ) being associated with increased APOC3 concentrations, underscoring the complex genetic architecture influencing lipid profiles. ^[1]

Genetic Variants and Cardioprotection

The identification of a null mutation, R19X, in the APOC3gene provides compelling evidence for its prognostic value in cardiovascular health.^[2]Individuals who are heterozygous carriers of this mutation express approximately 50% less apoC-III, resulting in a highly favorable plasma lipid profile characterized by significantly reduced fasting triglycerides and markedly elevated high-density lipoprotein cholesterol (HDL-C).^[2]This genetic advantage translates into a greater likelihood of achieving optimal low-density lipoprotein cholesterol (LDL-C) levels and high HDL-C, which is recognized as cardioprotective by clinical guidelines.^[2]Furthermore, these carriers exhibit substantially less subclinical coronary artery atherosclerosis, as quantified by lower coronary artery calcium (CAC) scores, indicating a significant reduction in long-term cardiovascular disease risk.^[2]

Therapeutic Strategies and Risk Stratification

The insights gained from APOC3 research offer promising avenues for personalized medicine and targeted prevention strategies. ^[2] The strong cardioprotective effect observed in individuals with naturally occurring APOC3 deficiency suggests that therapies designed to reduce APOC3levels could be highly effective in managing dyslipidemia and preventing cardiovascular events.^[2]Notably, several established lipid-lowering agents, including fibrates, statins, thiazolidinediones, ezetimibe, niacin, and fish oil, as well as lifestyle interventions like weight loss, have been shown to decrease apoC-III levels.^[2] This knowledge can be leveraged for improved risk stratification, enabling clinicians to identify high-risk individuals who may benefit most from specific APOC3-modulating therapies or intensified lipid management to optimize patient outcomes.

References

[1] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.

[2] Pollin, T.I., et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 326, no. 5951, 2009, pp. 434-437.

[3] Willer, Cristen J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nature Genetics, vol. 40, no. 2, 2008, pp. 161-169.

[4] Benjamin, Emelia J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, no. 1, 2007, p. S11.

[5] Ridker, Paul M., et al. “Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKRassociate with plasma C-reactive protein: the Women’s Genome Health Study.”American Journal of Human Genetics, vol. 82, no. 5, 2008, pp. 1185-92.

[6] Reiner, Alexander P., et al. “Polymorphisms of the HNF1Agene encoding hepatocyte nuclear factor-1 alpha are associated with C-reactive protein.”American Journal of Human Genetics, vol. 82, no. 5, 2008, pp. 1193-201.

[7] Vasan, Ramachandran S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, no. 1, 2007, p. S2.

[8] Sabatti, Chiara, et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nature Genetics, vol. 41, no. 1, 2009, pp. 35-46.

[9] Aalto-Setala, K., et al. “Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.”J. Clin. Invest., vol. 90, 1992, pp. 1889–1900.