Triglycerides In Ldl
Triglycerides in low-density lipoprotein (LDL) refer to the presence of triglyceride molecules within LDL particles. LDL, often referred to as “bad” cholesterol, is one of several types of lipoproteins that transport fats, including cholesterol and triglycerides, in the bloodstream. While LDL is primarily known for carrying cholesterol, it can also contain varying amounts of triglycerides.
Biological Basis
Section titled “Biological Basis”Lipoproteins are complex particles composed of lipids (fats) and proteins (apolipoproteins) that enable fats to be transported through the water-based bloodstream. Their primary function is to deliver energy (in the form of triglycerides) and building blocks (like cholesterol) to cells throughout the body. Very low-density lipoprotein (VLDL) particles are synthesized in the liver and are rich in triglycerides. As VLDL particles circulate, they lose triglycerides through the action of lipoprotein lipase, gradually transforming into intermediate-density lipoprotein (IDL) and eventually into LDL.
Under certain metabolic conditions, particularly when there is an excess of triglycerides in the blood, VLDL and other triglyceride-rich lipoproteins can exchange lipids with LDL particles. This process, mediated by cholesterol ester transfer protein (CETP), typically involves LDL particles acquiring triglycerides in exchange for cholesterol esters. This results in triglyceride-enriched LDL particles, which are then more susceptible to further modification by hepatic lipase, leading to the formation of smaller, denser LDL particles. The_GCKR_ P446L allele (rs1260326 ), for example, has been associated with increased concentrations of _APOC-III_, an inhibitor of triglyceride catabolism, suggesting a genetic influence on triglyceride metabolism.[1]
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of triglycerides within LDL particles, especially the formation of small, dense LDL, are considered a significant risk factor for cardiovascular disease. Small, dense LDL particles are thought to be more atherogenic (plaque-forming) than larger, buoyant LDL particles because they can more easily penetrate the arterial wall, are more susceptible to oxidation, and have a lower affinity for the_LDL_receptor, leading to a prolonged circulation time. The presence of these particles is often associated with other metabolic abnormalities, such as insulin resistance, obesity, and type 2 diabetes. While_LPA_ coding SNP rs3798220 has been associated with LDL cholesterol levels, the broader understanding of lipoprotein concentrations and their components, including triglycerides, is critical for assessing cardiovascular risk.[1]
Social Importance
Section titled “Social Importance”Understanding the role of triglycerides in LDL is crucial for public health initiatives aimed at preventing and managing cardiovascular disease, which remains a leading cause of mortality worldwide. Identifying individuals at risk through lipid panel testing and addressing elevated triglyceride levels within LDL through lifestyle modifications (diet, exercise) and, if necessary, pharmacological interventions, can significantly reduce the burden of heart disease. Research into the genetic factors influencing triglyceride and lipoprotein metabolism, such as those impacting_APOC-III_ and _LPA_levels, further contributes to personalized medicine approaches for cardiovascular risk assessment and treatment strategies.[1]
Limitations
Section titled “Limitations”Methodological and Phenotypic Nuances
Section titled “Methodological and Phenotypic Nuances”The analytical approaches and study designs varied across the numerous cohorts integrated into the meta-analyses. While efforts were made to standardize analyses, some cohorts had specific exclusions or adjustments, such as omitting age-squared or different outlier handling, which could introduce subtle inconsistencies in statistical power and effect size estimation.[1]Additionally, while some studies utilized population-based cohorts, others might have included subjects ascertained for specific disease traits, potentially leading to selection bias that could influence the generalizability of detected associations and their estimated impact at a population level.[2] Such methodological heterogeneity, despite rigorous meta-analytical techniques, can complicate the interpretation of combined results.
Variations in phenotype ascertainment protocols represent a notable limitation, particularly regarding the handling of lipid-lowering therapy and fasting status. Although many studies excluded individuals on such medications, some cohorts lacked this information, leading to the inclusion of treated individuals, which could confound genetic associations with baseline lipid levels. [3] Furthermore, while fasting samples were generally required, the precise duration of fasting varied, with some cohorts reporting a wide range of fasting times, which is especially problematic for triglycerides due to their sensitivity to recent dietary intake. [1] These inconsistencies in phenotype measurement can introduce variability and reduce the accuracy of genotype-phenotype correlations.
Generalizability and Ancestral Diversity
Section titled “Generalizability and Ancestral Diversity”The generalizability of findings concerning triglycerides in LDL is constrained by the predominant focus on populations of European ancestry across a majority of the discovery and replication cohorts.[2] Many studies explicitly excluded individuals of non-European descent, thereby limiting the direct applicability of these genetic insights to other global populations. [2] Although some research expanded to multiethnic cohorts, these instances were often secondary explorations, suggesting that the primary genetic associations and their effect sizes may differ in populations with distinct genetic backgrounds and environmental exposures. [1]This narrow ancestral focus necessitates further investigation across diverse populations to fully understand the global genetic architecture of triglyceride levels.
Unaccounted Variability and Complex Interactions
Section titled “Unaccounted Variability and Complex Interactions”A significant limitation is the concept of “missing heritability,” where the common genetic loci identified explain only a small fraction of the total variation in triglyceride levels within the population.[2] Specifically, for triglycerides, the proportion of variance explained by identified common variants was approximately 7.4%. [3]This suggests that a substantial portion of the genetic influences on triglyceride levels remains undiscovered, likely involving rarer variants, structural variations, epigenetic factors, or more complex gene-gene and gene-environment interactions not captured by standard GWAS methodologies. Therefore, the current genetic profiles are incomplete, indicating a need for continued gene discovery efforts with larger samples and improved statistical power.
Despite adjustments for key demographic and clinical variables like age, sex, and diabetes status, the potential impact of unmeasured environmental or lifestyle confounders remains a limitation. Factors such as dietary habits, physical activity levels, or other concomitant medications and comorbidities, which significantly influence triglyceride levels, were not consistently or comprehensively accounted for across all studies.[3]Such unmeasured variables can either mask true genetic effects or create spurious associations. The observation that adjusting for body mass index (BMI) revealed a specific locus association underscores the importance of considering these complex gene-environment interactions for a complete understanding of lipid metabolism. [4]
Variants
Section titled “Variants”Genetic variations play a crucial role in determining an individual’s lipid profile, including levels of triglycerides in low-density lipoprotein (LDL). Several genes are implicated in the complex pathways of lipid metabolism, affecting the synthesis, transport, and breakdown of lipoproteins. Variants within these genes can influence how the body processes fats, leading to different concentrations of circulating lipids.
Variants in key apolipoprotein and receptor genes, such as rs429358 in APOE, significantly impact LDL cholesterol and triglyceride levels. TheAPOEgene provides instructions for apolipoprotein E, a critical component of very low-density lipoprotein (VLDL) and chylomicron remnants, essential for their clearance from the bloodstream. Specific alleles ofrs429358 , such as the epsilon 4 allele, are well-known to impair the removal of triglyceride-rich lipoproteins and their remnants, leading to higher LDL cholesterol concentrations.[5] Similarly, variants like rs548145 and rs34722314 found in the APOB gene, which encodes the primary protein of LDL particles, can alter the structure or metabolism of these lipoproteins. Such variations in APOBcan affect LDL particle number and size, contributing to changes in LDL cholesterol and triglyceride levels.[1] Additionally, the LDLR gene, along with nearby genes such as SMARCA4, which is often co-located, influences the low-density lipoprotein receptor, a critical protein responsible for clearing LDL particles from the circulation. Variants likers115594766 near LDLRcan reduce receptor activity, leading to increased levels of circulating LDL cholesterol, and subsequently influencing triglyceride-rich lipoprotein metabolism.[2]
Other genetic variants primarily affect triglyceride metabolism. Thers1260326 variant in the GCKRgene, which encodes glucokinase regulatory protein, has a notable impact on triglyceride levels.GCKRregulates the activity of glucokinase, an enzyme that controls the first step of glucose metabolism in the liver, thereby influencing hepatic glucose utilization and de novo lipogenesis. The T allele ofrs1260326 is strongly associated with increased plasma triglyceride concentrations.[5] Furthermore, variants like rs28601761 and rs2954021 within the TRIB1(Tribbles Homolog 1) gene are linked to altered triglyceride levels.TRIB1plays a role in regulating mitogen-activated protein kinase pathways, which are integral to lipid metabolism, and its variations can influence the production and clearance of triglyceride-rich lipoproteins.[5] Another important variant is rs964184 , located near the APOA5-APOA4-APOC3-APOA1gene cluster, a region profoundly involved in triglyceride metabolism. The G allele ofrs964184 is strongly associated with a significant increase in triglyceride concentrations, primarily through the effects ofAPOA5on lipoprotein lipase activity.[5]
Beyond these key regulators, other genes contribute to the intricate network of lipid control. The ALDH1A2 gene, an aldehyde dehydrogenase, is involved in various metabolic pathways, including the synthesis of retinoic acid, which can indirectly influence lipid metabolism. Variants such as rs1601933 , rs4775033 , rs1318175 , and rs11632618 within ALDH1A2may subtly shift metabolic balances, potentially impacting overall triglyceride levels.[2] rs11632618 is also associated with the LIPCgene, which encodes hepatic lipase. This enzyme is crucial for hydrolyzing triglycerides and phospholipids in circulating lipoproteins, particularly affecting the metabolism of high-density lipoprotein (HDL) and remnants of triglyceride-rich lipoproteins. Variants inLIPC can alter enzyme activity, thereby influencing the composition and concentration of various lipoproteins, including LDL and triglycerides. [3] Lastly, the rs660240 variant within the CELSR2 gene is part of a genomic region (CELSR2-PSRC1-SORT1) consistently associated with LDL cholesterol levels. While CELSR2 itself is not directly implicated in lipid metabolism, other variants in this region are believed to influence the expression of SORT1, a gene that mediates the endocytosis and degradation of lipoprotein lipase, ultimately impacting LDL cholesterol and potentially triglyceride levels.[5]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Defining Triglycerides and Low-Density Lipoprotein Cholesterol
Section titled “Defining Triglycerides and Low-Density Lipoprotein Cholesterol”Triglycerides are a primary type of fat, or lipid, found in the blood and serve as the main form of energy storage in the body. They are a crucial component of blood lipid profiles, along with cholesterol. [1]Low-density lipoprotein (LDL) cholesterol, often referred to as “bad cholesterol,” represents the cholesterol primarily carried within LDL particles. These particles are responsible for transporting cholesterol from the liver to cells throughout the body, and elevated levels are strongly associated with increased cardiovascular risk.[2] While distinct entities, LDL particles themselves contain triglycerides, and concentrations of LDL cholesterol and triglycerides often exhibit a modest positive correlation. [6]This interplay is central to the broader concept of dyslipidemia, where both lipid types can be abnormally elevated. It is important to note that “true LDL” cholesterol measurements specifically exclude lipoprotein(a) cholesterol to ensure accurate assessment.[7]
Measurement Methodologies and Operational Definitions
Section titled “Measurement Methodologies and Operational Definitions”The assessment of triglyceride and LDL cholesterol levels relies on standardized measurement methodologies. Blood samples are typically collected after a period of fasting, often a minimum of four hours, to ensure accurate lipid concentration readings.[1]Lipid concentrations, including total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides, are commonly measured using standard enzymatic methods.[1]LDL cholesterol concentration is frequently calculated using empirical formulas, such as Friedewald’s formula, although missing values may be assigned or specific exclusions made for individuals with very high triglyceride levels, typically exceeding 400 mg/dl.[1]For research and statistical analyses, triglyceride values are often natural log-transformed to achieve a more normal distribution[8] and adjusted for potential confounding variables like age, age squared, gender, and diabetes status. [8] Furthermore, individuals who have not fasted, are diabetic, or are on lipid-lowering therapy are often excluded from studies evaluating baseline lipid traits. [4]
Classification, Clinical Context, and Terminology
Section titled “Classification, Clinical Context, and Terminology”The classification of triglyceride and LDL cholesterol levels is critical for clinical management and risk assessment, often adhering to guidelines such as those from the National Cholesterol Education Program (NCEP).[7] Normal ranges are established for both, with LDL-cholesterol typically falling between 60–129 mg/dl and triglycerides between 30–149 mg/dl. [7] Abnormal lipid levels are broadly categorized under the term dyslipidemia, which can manifest as polygenic dyslipidemia, influenced by multiple genetic factors, or rarer mendelian forms. [8]The clinical significance of elevated LDL cholesterol and triglyceride levels is profound, as they are well-established determinants of cardiovascular disease (CVD)[9]and coronary heart disease (CHD) risk[2] and are often components of the metabolic syndrome. [10] These lipid traits exhibit high heritability, underscoring the significant genetic influence on an individual’s lipid profile. [2]
Causes
Section titled “Causes”Genetic Predisposition to Dyslipidemia
Section titled “Genetic Predisposition to Dyslipidemia”Multiple genetic factors play a significant role in influencing the levels of triglycerides within lipoproteins, including low-density lipoprotein (LDL). Research indicates that dyslipidemia, a condition characterized by abnormal lipid levels, has a polygenic basis, meaning it is influenced by common variants across numerous genetic loci. Studies have identified as many as 30 such loci that collectively contribute to this complex trait, affecting various aspects of lipid and lipoprotein metabolism.[1]These inherited predispositions can lead to alterations in the synthesis, transport, and catabolism of lipids, ultimately impacting the concentration of triglycerides found in different lipoprotein particles, including remnant lipoproteins and LDL.
One notable genetic variant contributing to altered triglyceride metabolism is the P446L allele of theGCKR gene, identified by rs1260326 . This specific allele is associated with elevated concentrations of APOC-III. [1] APOC-III, a protein synthesized in the liver, acts as a crucial inhibitor of triglyceride catabolism.[1] By impeding the breakdown of triglycerides, an increase in APOC-III levels, driven by variants like rs1260326 , can lead to higher circulating triglyceride levels, which can then be found within various lipoprotein fractions, including LDL and remnant lipoproteins.
Biological Background
Section titled “Biological Background”Genetic Regulation of Triglyceride Synthesis and Lipid Homeostasis
Section titled “Genetic Regulation of Triglyceride Synthesis and Lipid Homeostasis”Triglyceride levels in the body are tightly controlled by a complex interplay of genetic and metabolic pathways. Variations near genes such asMLXIPL, ANGPTL3, and TRIB1have been identified as influencing triglyceride concentrations.[5] MLXIPL(MLX Interacting Protein Like) encodes a protein that plays a crucial role in activating specific regulatory elements within the promoters of genes involved in triglyceride synthesis, thereby directly impacting the cellular production of triglycerides.[5] Similarly, ANGPTL3 (Angiopoietin Like 3) is a major regulator of lipid metabolism, and its protein product helps maintain systemic lipid balance. [5] A related gene, ANGPTL4, also has rare variants associated with both high-density lipoprotein (HDL) and triglyceride concentrations in humans, highlighting the broader role of this gene family in lipid regulation.[5]
Intertwined Pathways of Cholesterol Synthesis and Degradation
Section titled “Intertwined Pathways of Cholesterol Synthesis and Degradation”The body’s management of cholesterol is closely linked to triglyceride metabolism, involving several key enzymatic steps and regulatory proteins. Two neighboring genes,MVK (Mevalonate Kinase) and MMAB (Methylmalonic Aciduria Type B), are central to these processes and are under the regulatory control of SREBP2 (Sterol Regulatory Element Binding Protein 2), sharing a common promoter region. [5] MVK encodes mevalonate kinase, an enzyme critical for catalyzing an early, rate-limiting step in the extensive cholesterol biosynthesis pathway. [5] Conversely, MMAB encodes a protein that participates in a metabolic pathway responsible for the degradation of cholesterol, thus collectively, these genes contribute to the overall maintenance of cholesterol homeostasis within cells and tissues. [5]
Cellular Glycosylation and Lipoprotein Modification
Section titled “Cellular Glycosylation and Lipoprotein Modification”The proper function of lipoproteins and their receptors, which are essential for lipid transport throughout the body, can be influenced by post-translational modifications such as glycosylation. GALNT2 (N-Acetylgalactosaminyltransferase 2) encodes a widely expressed glycosyltransferase enzyme. [5] This enzyme’s activity could potentially lead to modifications of lipoproteins themselves or the receptors that bind them, thereby altering their structure, stability, or recognition by other cellular components. [5]While the precise impact on triglycerides in LDL requires further elucidation, such modifications could affect how lipoproteins are processed, cleared, or interact with cells, influencing overall lipid dynamics.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Dynamic Interplay in Lipoprotein Remodeling
Section titled “Dynamic Interplay in Lipoprotein Remodeling”The intricate balance of plasma lipid levels, including the triglyceride content within low-density lipoproteins (LDL), is heavily influenced by a network of lipid transfer proteins and lipases. ThePhospholipid Transfer Protein (PLTP) plays a crucial role by facilitating the exchange of phospholipids and cholesterol esters between different lipoprotein classes, thereby influencing their composition and metabolism. For instance, studies have shown that in mice expressing humanPLTP and APOA1transgenes, there is an increase in prebeta-high density lipoprotein (HDL),APOA1, and total phospholipids, highlighting PLTP’s impact on HDL structure. [11] Conversely, a targeted mutation of the PLTPgene results in a marked reduction in HDL levels, underscoring its essential role in maintaining lipoprotein homeostasis.[12]This dynamic lipid remodeling directly impacts the availability of lipids for transfer, consequently affecting the triglyceride enrichment and overall stability of LDL particles in the circulation.
Another key enzyme governing lipoprotein metabolism and triglyceride content isHepatic Lipase (HL). HLacts as a triglyceride lipase and phospholipase, primarily hydrolyzing triglycerides and phospholipids within intermediate-density lipoproteins (IDL) and HDL. This activity is vital for the conversion of IDL to mature LDL particles, directly influencing the quantity of triglycerides associated with LDL.[13] Any modulation in HLactivity can lead to altered catabolism of triglyceride-rich lipoproteins, impacting the flux of triglycerides into and out of LDL, and thus contributing to dyslipidemic states characterized by triglyceride-enriched LDL.
Genetic Determinants and Regulatory Control of Lipid Homeostasis
Section titled “Genetic Determinants and Regulatory Control of Lipid Homeostasis”The regulation of enzymes critical for lipid metabolism, such as hepatic lipase, is a significant determinant of plasma lipid profiles, including the triglyceride levels in LDL. Genetic variations within the regulatory regions of these genes can profoundly affect their expression and function. For example, a polymorphism in thehepatic lipase promoter region, specifically the -514C->T variant, has been linked to variations in plasma lipid levels. [13] Such genetic alterations can lead to altered HLactivity, subsequently modulating the processing of triglyceride-rich lipoproteins and thus the triglyceride content within LDL particles. These changes represent a form of genetic regulatory mechanism that impacts overall metabolic flux.
Furthermore, the complexity of lipid disorders like dyslipidemia is often characterized by a polygenic etiology, where multiple common genetic variants contribute to the overall phenotype. Research has identified common variants at numerous loci that collectively influence susceptibility to polygenic dyslipidemia. [1]This systems-level integration of genetic factors suggests that the triglyceride content of LDL is not merely controlled by single pathways but by hierarchical regulation and network interactions, where subtle changes across many genes can cumulatively lead to significant dysregulation of lipoprotein metabolism. Understanding these genetic contributions is crucial for deciphering the emergent properties of lipid metabolism in health and disease.
Therapeutic and Nutritional Modulators of Hypertriglyceridemia
Section titled “Therapeutic and Nutritional Modulators of Hypertriglyceridemia”Beyond endogenous genetic and enzymatic controls, exogenous factors, particularly dietary components, exert substantial influence over systemic lipid metabolism and triglyceride levels. Dietary interventions, specifically the intake of fish oils rich in omega-3 fatty acids, have been shown to significantly reduce plasma lipids, lipoproteins, and apoproteins in patients presenting with hypertriglyceridemia.[14]This robust reduction suggests a powerful metabolic regulation mechanism, likely involving a decrease in the hepatic biosynthesis of very-low-density lipoproteins (VLDL) and an enhancement of triglyceride catabolism. Such a modulation in overall triglyceride homeostasis would consequently impact the pool of triglycerides available for transfer to and from LDL particles, presenting a key therapeutic target for managing triglyceride-related dyslipidemias.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Underpinnings of Combined Dyslipidemia
Section titled “Genetic Underpinnings of Combined Dyslipidemia”The clinical relevance of ‘triglycerides in LDL’ is largely understood through the shared genetic predispositions and biological pathways that influence both triglyceride and low-density lipoprotein (LDL) cholesterol levels, often presenting as combined dyslipidemia. Research has identified specific genetic loci where variations can simultaneously affect the concentrations of both lipid components. For example, a single nucleotide polymorphism (rs16996148 ) located near CILP2has demonstrated a strong association with both increased LDL cholesterol concentrations and increased triglyceride concentrations. The allele linked to elevated LDL cholesterol is consistently associated with higher triglycerides, highlighting a modest but significant positive correlation between these two traits and suggesting complex, overlapping metabolic regulation.[5] These genetic insights are crucial for understanding the etiology of dyslipidemia and recognizing that managing one lipid parameter may have implications for others.
Predictive Value for Atherosclerosis and Coronary Heart Disease
Section titled “Predictive Value for Atherosclerosis and Coronary Heart Disease”The interplay between triglycerides and LDL cholesterol carries significant prognostic value for major cardiovascular outcomes, including atherosclerosis and coronary heart disease (CHD). Elevated triglyceride levels, irrespective of fasting status, have been shown to correlate with an increased risk of cardiovascular events, underscoring their independent role in disease progression.[15]Furthermore, specific genetic variants that lead to increased triglyceride concentrations, such as those near theTRIB1 gene (e.g., rs17321515 ), have also been directly associated with an increased risk of CAD. [5]This evidence establishes that genetic factors influencing triglyceride and LDL cholesterol levels have long-term implications for a patient’s risk profile, necessitating their comprehensive assessment in cardiovascular risk prediction and management.
Enhancing Risk Assessment and Personalized Prevention
Section titled “Enhancing Risk Assessment and Personalized Prevention”Understanding the genetic architecture behind the co-occurrence of high triglycerides and LDL cholesterol offers powerful tools for refining individual risk stratification and implementing personalized prevention strategies. Genetic risk scores, which integrate multiple genetic variants associated with various lipid levels including triglycerides and LDL cholesterol, have demonstrated an ability to improve the classification of CHD risk beyond traditional clinical factors such as age, body mass index, and sex.[2]Although a genetic risk score for total cholesterol has been particularly noted for its predictive power in identifying individuals at risk for atherosclerosis and CHD, the broader application of genetic profiling helps in identifying individuals with a heightened predisposition to dyslipidemia and its associated complications.[2]Such advancements in risk assessment can guide the selection of more targeted interventions, inform treatment decisions, and enable tailored monitoring strategies, moving healthcare closer to a truly personalized approach in cardiovascular disease prevention.
References
Section titled “References”[1] Kathiresan S et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008.
[2] Aulchenko YS et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009.
[3] Kathiresan S et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009.
[4] Sabatti C et al. Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet. 2008.
[5] Willer CJ et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008.
[6] Willer, CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 1, 2008a, pp. 161-169.
[7] 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. 5, 2009, pp. 883-93.
[8] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 1, 2008a, pp. 189-97.
[9] Benjamin, EJ, et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, 2007, p. 55.
[10] Kooner, JS, et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, vol. 40, no. 2, 2008, pp. 149-51.
[11] Jiang, XC., 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. 98, no. 10, 1996, pp. 2373–2380.
[12] Jiang, XC., et al. “Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.”J. Clin. Invest., vol. 103, no. 5, 1999, pp. 907–914.
[13] Isaacs, A., et al. “The -514C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.” J. Clin. Endocrinol. Metab., vol. 89, no. 8, 2004, pp. 3858–3863.
[14] Phillipson, BE., et al. “Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia.” N. Engl. J. Med., vol. 312, no. 19, 1985, pp. 1210–1216.
[15] Wallace, C., et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”American Journal of Human Genetics, vol. 82, no. 1, 2008, pp. 132–137.