Triglycerides In Medium Ldl
Introduction
Section titled “Introduction”Background
Section titled “Background”Triglycerides are a type of fat (lipid) that circulates in the bloodstream and serves as a major energy source for the body. Low-density lipoprotein (LDL) particles are critical transporters of cholesterol and, to a lesser extent, triglycerides throughout the body. LDL particles are not uniform; they exist in various subfractions differing in size, density, and lipid composition, commonly classified as large, medium, and small. The specific amount of triglycerides carried within medium LDL particles is a distinct lipid characteristic that can provide more detailed insights into an individual’s metabolic health.
Biological Basis
Section titled “Biological Basis”Triglycerides are packaged into lipoprotein particles, including LDL, for transport between tissues. The primary structural component of LDL particles is apolipoprotein B (APOB). The metabolism of these triglycerides involves complex enzymatic processes. For example, apolipoprotein C-III (APOC-III), which is synthesized in the liver, functions as an inhibitor of triglyceride catabolism, meaning it slows down the breakdown of triglycerides.[1] Genetic variations can influence the levels of APOC-IIIand other proteins, thereby affecting the triglyceride content within various lipoprotein subfractions, including medium LDL particles.[1]
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of triglycerides, especially within specific LDL subfractions like medium LDL, are considered a risk factor for cardiovascular diseases, including atherosclerosis. Studies suggest that certain LDL subfractions, particularly smaller, denser particles and those enriched with triglycerides, may be more atherogenic. Therefore, assessing triglycerides in medium LDL provides a more refined understanding of an individual’s lipid profile and cardiovascular risk compared to total LDL cholesterol alone. This detailed lipid information can aid in the diagnosis and management of dyslipidemia.
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of morbidity and mortality globally, posing a significant public health challenge. A deeper understanding of specific lipid traits, such as triglycerides in medium LDL, and their genetic determinants contributes to the development of more precise risk assessment tools and targeted interventions. Identifying individuals with a genetic predisposition to altered triglyceride levels in medium LDL can inform personalized strategies for prevention, including lifestyle modifications and pharmacological treatments, ultimately aiming to reduce the societal burden of cardiovascular disease.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The studies largely relied on an additive model of inheritance for genotype-triglycerides association analyses, which may oversimplify the complex genetic architecture of lipid traits and potentially miss non-additive effects or gene-gene interactions. While combining data from multiple large cohorts in meta-analyses enhanced statistical power, some of these cohorts were initially recruited based on specific disease ascertainments, such as diabetes. This selective recruitment could introduce a degree of bias, potentially affecting the generalizability of detected associations and the precise estimation of their population-level impact.[2]
Inconsistencies in phenotype adjustment across participating studies further complicate the interpretation of findings, particularly regarding the handling of individuals on lipid-lowering therapy. Although many studies excluded subjects receiving such treatment, some cohorts lacked this information or treated it inconsistently, introducing potential confounding that could mask or distort genetic effects. Furthermore, the reliance on calculated LDL cholesterol values using the Friedewald formula, especially for individuals with very high triglyceride levels where direct measurement was not available, might lead to inaccuracies in related lipid phenotypes.[2]
Generalizability and Phenotype Measurement Precision
Section titled “Generalizability and Phenotype Measurement Precision”A significant limitation of the research is the predominant inclusion of populations of European ancestry across the majority of discovery and replication cohorts. Although one study made an effort to extend findings to a multiethnic sample, the generalizability of identified genetic associations for triglycerides to diverse global populations, including those of Chinese, Malay, or Asian Indian descent, remains largely under-explored. This limited ethnic diversity restricts the direct applicability of the discovered loci to non-European ancestral groups and may overlook population-specific genetic variants or differential effect sizes influenced by unique genetic backgrounds and environmental exposures. [2]
Despite efforts to standardize lipid concentrations, subtle variations in the methodology for collecting and processing blood samples could affect the precision of triglyceride values. For instance, while some studies mandated fasting blood samples, at least one cohort allowed a broader fasting window, ranging from a minimum of four hours to an average of six hours. Such variability in fasting duration is known to influence triglyceride levels, thereby introducing noise into the phenotype data and potentially attenuating or confounding genetic associations with triglycerides.[2]
Unexplained Variance and Complex Genetic Architectures
Section titled “Unexplained Variance and Complex Genetic Architectures”The currently identified common genetic loci explain only a small fraction of the total variability in triglycerides within the population, accounting for approximately 7.4% of the variance. This substantial “missing heritability” indicates that a vast proportion of the genetic and environmental influences contributing to triglyceride concentrations remains unaccounted for. This suggests that numerous other genetic factors, including rarer variants, structural variations, or complex epistatic interactions, significantly contribute to lipid levels and are yet to be fully elucidated.[3]
The studies primarily adjusted for basic demographic and clinical covariates like age, sex, and diabetes status, but did not extensively account for a broader spectrum of environmental or lifestyle confounders such as specific dietary habits, levels of physical activity, or other detailed environmental exposures. The potential for gene-environment interactions, where genetic predispositions are modulated by environmental factors, was largely unexplored. Furthermore, the observation that some loci demonstrate different impacts between males and females indicates that the genetic architecture of lipid traits is more intricate than a simple additive model, necessitating further investigation into sex-specific effects and other nuanced interactions.[3]
Variants
Section titled “Variants”The genetic variants influencing lipid metabolism play a significant role in determining an individual’s triglyceride levels, particularly within medium-density low-density lipoprotein (LDL) particles. These variants are found in genes involved in the synthesis, processing, and clearance of various lipoproteins. Understanding their impact can provide insights into cardiovascular disease risk.
The APOE(Apolipoprotein E) gene is essential for the metabolism of triglyceride-rich lipoproteins and their remnants, playing a key role in guiding these particles, including those found in medium LDL, to liver receptors for clearance. Thers429358 variant, a component of the common APOEgene variants (e.g., E2, E3, E4 alleles), significantly influences lipoprotein metabolism. Individuals carrying certain alleles defined byrs429358 can exhibit altered clearance of triglyceride-rich lipoproteins and elevated LDL cholesterol, which may contribute to higher triglycerides in medium LDL particles. . For accurate measurement in clinical and research settings, triglyceride concentrations are typically determined from fasting blood samples[4]. [1]In genetic association studies, triglyceride values are often natural log-transformed to meet statistical assumptions and account for their skewed distribution[1], [4]. [3]
Low-density lipoprotein cholesterol (LDL cholesterol) represents cholesterol transported by LDL particles, often referred to as “bad” cholesterol due to its association with cardiovascular risk.[3]The operational definition of “true LDL” in some contexts specifically excludes lipoprotein(a) cholesterol, highlighting the complexity of lipoprotein composition.[5] Similar to triglycerides, LDL cholesterol concentrations are determined from fasting blood samples and are commonly calculated using the Friedewald’s formula [4]with missing values assigned for individuals with very high triglyceride levels (e.g., >400 mg/dl) where the formula may be less accurate.[4]These lipids are crucial components of an individual’s overall lipid profile, with very low-density lipoprotein (VLDL) cholesterol also routinely measured as part of this assessment.[5]
Key Variants
Section titled “Key Variants”Clinical Categorization and Assessment of Lipid Levels
Section titled “Clinical Categorization and Assessment of Lipid Levels”The clinical classification and assessment of triglyceride and LDL cholesterol levels are guided by established diagnostic criteria and thresholds, notably those provided by organizations such as the National Cholesterol Education Program.[5] For triglycerides, a normal range is considered to be between 30 and 149 mg/dl. [5] Levels outside this range can indicate dyslipidemia, a condition characterized by abnormal lipid levels that are significant risk factors for various health issues. [1]
For LDL cholesterol, the normal range is typically defined as 60–129 mg/dl. [5]These cut-off values serve as clinical criteria for identifying individuals at increased risk for cardiovascular disease (CVD), guiding decisions regarding lifestyle interventions or medication therapy.[6] In research studies, participants on lipid-lowering therapy are frequently excluded from analyses to prevent confounding of natural lipid concentrations and genetic associations, ensuring that the measured lipid levels reflect underlying biological and genetic influences [4]. [1]
Physiological Significance and Genetic Underpinnings of Lipid Homeostasis
Section titled “Physiological Significance and Genetic Underpinnings of Lipid Homeostasis”Triglycerides and LDL cholesterol are fundamental determinants of cardiovascular disease morbidity, underscoring their critical role in physiological processes and disease pathogenesis.[3] Both lipid traits are recognized as highly heritable, with a significant proportion of variation in their circulating levels attributable to genetic factors. [3] The study of these intermediate phenotypes provides a conceptual framework for understanding the pathway from genetic predisposition and standard risk factors to overt CVD .
Advanced genomic studies have identified numerous genetic loci associated with variations in triglyceride and LDL cholesterol levels, revealing complex polygenic contributions to dyslipidemia[1]. [3] For triglycerides, key genes include APOA5, GCKR, LPL, TRIB1, MLXIPL, and APOB [7], [8]. [4] For LDL cholesterol, significant associations have been found with genes such as APOE/APOC cluster, APOB, CELSR2, PSRC1, SORT1, LDLR, NCAN, and HMGCR [8], [9]. [3] The terminology “Metabolic Syndrome” also encompasses elevated triglycerides as one of its diagnostic criteria, further linking lipid profiles to broader metabolic health. [4]
Causes
Section titled “Causes”Polygenic Architecture of Lipid Metabolism
Section titled “Polygenic Architecture of Lipid Metabolism”Triglyceride levels within medium-density lipoproteins (LDL) are influenced by a complex interplay of numerous genetic factors. Research indicates that common genetic variants found across approximately 30 distinct genomic regions contribute significantly to a broader condition known as polygenic dyslipidemia. This suggests that an individual’s predisposition to elevated triglycerides, including those associated with medium LDL, is not typically due to a single gene defect but rather the cumulative effect of many small genetic variations inherited across the genome.[1]
This polygenic basis underlies the variability in an individual’s lipid profile, impacting the concentrations of various apolipoproteins like APOA-I, APOB, APOC-III, and APOE, as well as different lipoprotein particles and their triglyceride content. The combined impact of these common variants helps to explain why some individuals are more prone to elevated triglycerides in medium LDL, highlighting the inherited component of lipid metabolism regulation and its systemic effects on lipoprotein profiles.[1]
Genetic Determinants of Triglyceride Catabolism
Section titled “Genetic Determinants of Triglyceride Catabolism”Specific genetic variants play a direct and mechanistic role in regulating the breakdown of triglycerides in the body. For instance, the P446L allele of the GCKR gene (rs1260326 ) has been found to be significantly associated with increased concentrations of APOC-III. [1] Each copy of the Leu allele for this variant is linked to a measurable increase in APOC-III levels, indicating a clear genetic influence on the abundance of this key apolipoprotein.
The mechanism by which this genetic variant impacts triglycerides in medium LDL is throughAPOC-III’s function as an inhibitor of triglyceride catabolism. Synthesized primarily in the liver, elevated levels ofAPOC-III hinder the body’s ability to efficiently break down triglycerides, leading to their accumulation in the bloodstream. [1]This reduced catabolic efficiency directly contributes to higher circulating triglyceride levels, which can then be found within various lipoprotein fractions, including medium LDL particles.
Biological Background
Section titled “Biological Background”Molecular Pathways of Lipid Synthesis and Degradation
Section titled “Molecular Pathways of Lipid Synthesis and Degradation”The regulation of lipid concentrations, including triglycerides in medium LDL, involves complex molecular and cellular pathways essential for metabolic homeostasis. One critical pathway involves the protein encoded byMLXIPL, which plays a direct role in triglyceride synthesis. This protein specifically binds to and activates certain DNA sequences within the promoter regions of genes responsible for synthesizing triglycerides, thereby upregulating their production.[8]This mechanism directly influences the cellular capacity for triglyceride accumulation. Concurrently, cholesterol metabolism, intricately linked with triglyceride processing, involves enzymes like mevalonate kinase, encoded byMVK. Mevalonate kinase catalyzes an early and rate-limiting step in the mevalonate pathway, which is the primary route for cholesterol biosynthesis. [8] Complementing this, the protein encoded by MMAB participates in a metabolic pathway responsible for the degradation of cholesterol, ensuring a balanced removal of this lipid. [8]These interconnected pathways highlight the cellular machinery involved in both the anabolism and catabolism of essential lipids that ultimately impact circulating lipoprotein composition.
Genetic and Transcriptional Control of Lipid Genes
Section titled “Genetic and Transcriptional Control of Lipid Genes”The expression of genes involved in lipid metabolism is under tight genetic and transcriptional control, influencing an individual’s triglyceride levels in medium LDL. The regulation of triglyceride synthesis genes by theMLXIPL protein exemplifies a key genetic mechanism, where the MLXIPL protein acts as a transcription factor by binding to specific promoter motifs, thereby activating gene expression. [8] Furthermore, the neighboring genes MVK and MMAB, crucial for cholesterol biosynthesis and degradation respectively, share a common promoter and are both regulated by the transcription factor SREBP2. [8] This coordinated regulation by SREBP2 ensures a synchronized control over cholesterol levels, illustrating how specific regulatory elements and transcription factors orchestrate metabolic processes. Genetic variations, such as rare variants in ANGPTL4, a gene related to ANGPTL3, have been associated with alterations in both HDL and triglyceride concentrations in humans, demonstrating the direct genetic influence on lipid phenotypes.[8]
Systemic Regulation and Lipoprotein Modification
Section titled “Systemic Regulation and Lipoprotein Modification”Systemic lipid homeostasis and the characteristics of lipoproteins, such as medium LDL, are significantly influenced by a network of regulatory proteins and post-translational modifications. The protein homolog of ANGPTL3serves as a major regulator of lipid metabolism, playing a broad role in controlling circulating lipid levels and lipoprotein dynamics.[8]Its regulatory effects underscore a systemic influence on how lipids are processed and transported throughout the body, impacting the composition of various lipoprotein particles. Another key player,GALNT2, encodes a widely expressed glycosyltransferase, an enzyme capable of attaching sugar molecules to other proteins or lipids. [8] This enzymatic activity could potentially modify the structure or function of lipoproteins or their corresponding receptors, thereby affecting their stability, recognition, or cellular uptake. Such modifications could ultimately alter the half-life and content of triglycerides within circulating lipoproteins, including those found in the medium LDL fraction, highlighting the intricate interplay between enzyme function and systemic lipid flux.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Regulation of Lipid Synthesis and Catabolism
Section titled “Regulation of Lipid Synthesis and Catabolism”The regulation of plasma triglycerides and low-density lipoprotein (LDL) involves a complex interplay of synthesis, breakdown, and transport pathways.MLXIPLencodes a protein that directly binds to and activates specific motifs in the promoters of genes responsible for triglyceride synthesis[8]thereby influencing the overall cellular triglyceride pool. Cholesterol metabolism is similarly regulated, withMVK catalyzing an early step in its biosynthesis, while MMAB participates in a metabolic pathway for cholesterol degradation. [8] The catabolism of triglycerides from lipoproteins is critically dependent on lipases such as LPL, LIPC, and LIPG [8] whose activities are potent targets for regulation by proteins like ANGPTL3 and ANGPTL4, which act as inhibitors of lipoprotein lipase.[8]
Apolipoproteins are integral components governing the fate and function of lipoproteins. Genes encoding apolipoproteins such as APOA5, APOA4, APOC3, APOA1, APOB, and those within the APOE cluster are crucial for the proper formation, activity, and turnover of very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL. [8] For instance, increased levels of APOC3 can lead to hypertriglyceridemia by diminishing the fractional catabolic rate of VLDL particles, which are precursors to LDL, partly due to reduced APOE on these particles. [10] The LDLR plays a central role in clearing circulating lipoproteins, directly impacting plasma LDL concentrations. [8]
Transcriptional Control and Genetic Modulators
Section titled “Transcriptional Control and Genetic Modulators”Lipid homeostasis is heavily influenced by transcriptional control mechanisms that dictate the expression of genes involved in metabolic pathways. Transcription factors, such as MLXIPL, are central to this regulation, directly activating the transcription of genes necessary for triglyceride synthesis.[8] Another key regulator, SREBP2, orchestrates the expression of genes involved in cholesterol metabolism, including MVK and MMAB. [8] These transcriptional networks ensure a coordinated response to metabolic demands and nutrient availability, maintaining lipid balance.
Furthermore, interactions between transcription factors and lipoprotein-related proteins add another layer of regulatory complexity. For example,MAFB, a transcription factor, has been shown to interact with LDL-related protein [1] suggesting potential regulatory effects on LDL metabolism or cellular lipid uptake. The gene HAVCR1 is also annotated as a target for the transcription factor TCF1 [1] indicating a role in gene regulation that might indirectly influence lipid processing or inflammatory responses related to dyslipidemia. Genetic variations influencing these transcription factors and their targets can alter gene expression profiles, leading to observable changes in circulating lipid levels.
Post-translational Modification and Receptor Dynamics
Section titled “Post-translational Modification and Receptor Dynamics”Beyond gene expression, post-translational modifications and specific receptor interactions are critical for the functional regulation of proteins involved in lipid metabolism. Glycosyltransferases, such as those encoded by GALNT2, are widely expressed and can modify lipoproteins or their receptors. [8] This O-linked glycosylation has a regulatory role for many proteins [1]potentially impacting lipoprotein stability, receptor binding affinity, or enzymatic activity, thereby affecting circulating triglyceride and LDL levels. Such modifications can fine-tune the interactions between lipoproteins and their cellular targets.
Receptor-mediated endocytosis and degradation processes are also vital for clearing lipoproteins and their components. SORT1, also known as neurotensin receptor-3, actively binds and mediates the degradation of LPL [8] thereby directly impacting the rate at which triglycerides are hydrolyzed and cleared from the circulation. Additionally, TIMD4 and HAVCR1 have been identified as phosphatidylserine receptors on macrophages [1] facilitating the engulfment of apoptotic cells. This mechanism could be relevant to the clearance of lipid-laden cells or modified lipoproteins, influencing systemic lipid dynamics.
Interconnected Metabolic and Signaling Networks
Section titled “Interconnected Metabolic and Signaling Networks”The pathways governing triglycerides and LDL are deeply interconnected, forming integrated metabolic and signaling networks that maintain lipid homeostasis. Genes like TRIB1 encode a G-protein–coupled receptor-induced protein that is involved in regulating mitogen-activated protein kinases (MAPKs). [8] This suggests that TRIB1 may regulate lipid metabolism through such signaling pathways, indicating a broader role for cell signaling in controlling lipid processing and cellular responses to lipid changes. The coordinated activity of various enzymes, transporters like ABCA1 and CETP, and apolipoproteins illustrates a highly integrated system. [8]
This systems-level integration ensures that genetic influences on lipid metabolism are robust and can manifest under different physiological conditions. For example, genetic polymorphisms that affect fasting lipid levels have also been shown to exert their effects in the more common “fed” state. [11]This demonstrates the persistent impact of underlying genetic mechanisms on metabolic phenotypes and underscores the importance of considering the entire metabolic network rather than isolated pathways. Dysregulation within these interconnected pathways contributes to dyslipidemia and an increased risk of cardiovascular events.[11]
Clinical Relevance
Section titled “Clinical Relevance”Assessing Cardiovascular Risk and Outcomes
Section titled “Assessing Cardiovascular Risk and Outcomes”Triglyceride levels serve as crucial biomarkers for evaluating an individual’s risk of developing cardiovascular diseases. Elevated triglyceride concentrations, whether measured in a fasting or non-fasting state, are consistently associated with an increased risk of adverse cardiovascular events.[11]Current clinical practice incorporates screening for elevated lipid levels, including triglycerides, as a primary strategy for cardiovascular risk prevention.[3]Furthermore, while the genetic risk scores for various lipid traits (including triglycerides) provide explanatory value, studies suggest that for incident coronary heart disease (CHD), the predictive power of these genetic scores often does not significantly improve beyond that offered by circulating triglyceride levels themselves, implying that these lipid concentrations are on the causal pathway between genetic variants and disease outcomes.[3]
Nonetheless, combining a genetic risk profile with traditional clinical risk factors such as age, body mass index, sex, and existing lipid values has been shown to improve overall CHD risk classification, highlighting the utility of a comprehensive approach to patient risk stratification.[3]This integrated assessment allows for a more personalized understanding of an individual’s long-term cardiovascular prognosis and can guide targeted prevention strategies. Identifying high-risk individuals through such combined approaches enables earlier interventions, including dietary modifications and pharmacotherapy like statins, to mitigate the progression of atherosclerosis and related complications.[3]
Clinical Measurement and Management Strategies
Section titled “Clinical Measurement and Management Strategies”The diagnostic utility of triglyceride measurement is well-established in clinical practice, with concentrations typically assessed from fasting blood samples using standard enzymatic methods. A normal range for triglycerides is generally considered to be 30–149 mg/dl.[5]However, emerging evidence also underscores the significance of non-fasting triglyceride levels, which have been linked to an increased risk of cardiovascular events, suggesting that clinical assessment may extend beyond the traditional fasting state.[11]
Monitoring triglyceride levels is integral to evaluating the effectiveness of lifestyle interventions, such as dietary changes, and pharmacological treatments aimed at lipid lowering. For instance, individuals on lipid-lowering therapies are often excluded from genetic association studies to avoid confounding, yet managing these levels remains a cornerstone of preventing cardiovascular disease.[1]While the provided context does not detail specific triglyceride-lowering medications, the general emphasis on early treatment with statins and dietary changes underscores the importance of ongoing monitoring to guide and adjust therapeutic strategies, ultimately improving patient care outcomes.[3]
Genetic Determinants and Complex Dyslipidemias
Section titled “Genetic Determinants and Complex Dyslipidemias”Genetic studies have significantly advanced the understanding of the heritability of circulating lipid levels, including triglycerides, which are important determinants of cardiovascular morbidity.[3]Several genetic loci have been identified as contributors to triglyceride concentrations. Notable examples include variants nearTBL2 and MLXIPL on chromosome 7q11, TRIB1 on 8q24, GALNT2 on 1q42, CILP2-PBX4 on 19p13, and ANGPTL3 on 1p31, with additional associations found at APOA5, GCKR, and LPL. [4] The MLXIPL gene, in particular, has been identified in genome-wide scans as associated with plasma triglycerides. [7]
These genetic insights often highlight the polygenic nature of dyslipidemia, where multiple genes collectively influence lipid phenotypes. For example, a single nucleotide polymorphism (rs16996148 ) near CILP2has been strongly associated with both increased LDL cholesterol and increased triglyceride concentrations, demonstrating overlapping genetic influences on different lipid traits.[8]Such findings illustrate how genetic variants can impact lipid metabolism pathways that affect multiple lipoprotein classes, leading to complex dyslipidemic profiles. While many common loci have been identified, they currently explain only a small fraction of the total variation in lipid concentrations within the population, suggesting that much of the genetic architecture of triglyceride regulation remains to be discovered.[3]
References
Section titled “References”[1] Kathiresan S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet.
[2] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 12, 2008, pp. 1422-1429.
[3] Aulchenko YS et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet.
[4] 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. 34–46.
[5] Ober, C., et al. “Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q.”J Lipid Res, vol. 50, no. 3, 2009, pp. 448-456.
[6] O’Donnell, C. J., et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, pp. S10.
[7] Kooner JS et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet. 2008 Feb;40(2):149-51.
[8] Willer CJ et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet. 2008; 40:161–169.
[9] 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. 12, 2008, pp. 2315-2323.
[10] 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. 1992; 90:1889–1900.
[11] Wallace C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet. 2008; 82:131–142.