Triglycerides In Very Large Vldl
Introduction
Section titled “Introduction”Background
Section titled “Background”Triglycerides are the primary form of fat stored in the body and a major source of energy. They are transported in the bloodstream within lipoprotein particles. Very low-density lipoproteins (VLDL) are a class of these particles predominantly responsible for carrying triglycerides synthesized in the liver to various tissues for energy or storage. Very large VLDL specifically refers to the largest and most triglyceride-rich subtype of these particles, often contributing significantly to overall triglyceride levels. Elevated levels of triglycerides, especially within very large VLDL, are a key component of dyslipidemia, a condition characterized by unhealthy lipid profiles.
Biological Basis
Section titled “Biological Basis”The liver synthesizes triglycerides and packages them into VLDL particles for circulation. Once in the bloodstream, VLDL particles deliver their triglyceride payload to peripheral tissues through the action of lipoprotein lipase, an enzyme that breaks down triglycerides into fatty acids that can be absorbed by cells. After releasing much of their triglyceride content, VLDL particles become smaller, denser remnant lipoproteins. The regulation of triglyceride metabolism is complex, involving numerous proteins and enzymes. For instance,APOC-III(apolipoprotein C-III) is a protein synthesized in the liver that acts as an inhibitor of triglyceride catabolism.[1] This means higher levels of APOC-III can slow down the breakdown of triglycerides, leading to their accumulation in VLDL particles, including the very large VLDL subtype. Genetic variations, such as the GCKR P446L allele (rs1260326 ), have been associated with increased concentrations of APOC-III [1]thereby influencing triglyceride levels.
Clinical Relevance
Section titled “Clinical Relevance”Levels of triglycerides in very large VLDL are clinically relevant as they are a significant indicator of metabolic health and cardiovascular risk. Elevated triglycerides in these large, buoyant particles are often associated with an increased risk of developing cardiovascular diseases, including atherosclerosis, myocardial infarction, and stroke. They are also frequently observed in individuals with metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease. Assessing very large VLDL triglycerides can offer a more refined understanding of an individual’s lipid profile beyond total triglyceride levels, potentially identifying those at higher risk who might benefit from targeted interventions. Comprehensive lipid analyses often include the measurement of remnant lipoprotein triglycerides, which are closely related to the triglyceride content of very large VLDL.
Social Importance
Section titled “Social Importance”The prevalence of dyslipidemia and associated metabolic conditions represents a substantial global public health challenge. Understanding the factors that contribute to elevated triglycerides in very large VLDL is crucial for developing effective prevention and treatment strategies. Genetic insights into how variations in genes likeGCKRinfluence triglyceride metabolism andAPOC-IIIlevels can help identify individuals at higher genetic risk. This knowledge can inform personalized medicine approaches, allowing for earlier risk assessment, more precise lifestyle recommendations, and tailored therapeutic interventions, ultimately aiming to reduce the burden of cardiovascular disease and improve overall public health.
Limitations
Section titled “Limitations”Limited Generalizability and Phenotypic Standardization
Section titled “Limited Generalizability and Phenotypic Standardization”A primary limitation of the current understanding of triglyceride genetics lies in the demographic scope of the cohorts studied. The majority of participants in the large-scale genome-wide association studies were of European ancestry, with individuals of non-European descent often being excluded from analyses.[2] While some efforts were made to replicate findings in multiethnic cohorts [1] the findings may not be fully generalizable to the diverse global population. This presents a crucial challenge for understanding the complete spectrum of genetic influences on triglycerides across different ancestral backgrounds and clinical contexts.
Further limitations arise from inconsistencies in phenotypic measurement and data handling across various studies. Although triglycerides were consistently log-transformed for analysis, critical variables such as fasting duration varied between cohorts, and the handling of individuals on lipid-lowering therapy was not uniform. [1] Some studies excluded individuals receiving such treatments, while others lacked this information or did not deem exclusion necessary due to the historical context of the cohort [1]. [3] These differences in measurement protocols and exclusion criteria can introduce heterogeneity, potentially impacting the comparability of results and the overall precision of genetic associations identified.
Incomplete Genetic Architecture and Missing Heritability
Section titled “Incomplete Genetic Architecture and Missing Heritability”Despite the identification of numerous genetic loci associated with triglyceride levels, these common variants explain only a small fraction of the trait’s total variation within the population. Research indicates that the identified loci account for approximately 7.4% of the variance in triglycerides[3] and around 6% of total variability for metabolic traits more broadly. [4]This substantial “missing heritability” suggests that a large proportion of the genetic and potentially environmental factors contributing to triglyceride levels remain undiscovered.[2]
The modest effect sizes of individual common alleles, often observed to vary inversely with allele frequency, imply that many more genetic factors, potentially including rare variants or those with complex epistatic interactions, contribute to the polygenic architecture of triglycerides. [1] The current genetic profiles are thus far from complete, highlighting the need for continued research with advanced methodologies and even larger or more diverse cohorts to fully characterize the genetic influences on triglycerides and uncover the remaining sources of variability. [2]
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Certain methodological and statistical choices within the studies may limit the comprehensive interpretation of results. Some cohorts included individuals ascertained for specific diseases, such as diabetes, rather than being purely population-based. [2] Such ascertainment can introduce a selection bias, potentially affecting the generalizability of detected associations and their estimated impact at the population level. [2] While meta-analyses mitigated some of this by combining diverse cohorts, this inherent bias in initial study designs warrants consideration when extrapolating findings.
Furthermore, while the studies involved large sample sizes and rigorous statistical approaches, including meta-analyses and genomic control corrections [2], [3]the ongoing quest for “larger samples and improved statistical power” underscores persistent limitations in fully characterizing the genetic landscape. [3]The assumption of an additive mode of inheritance for gene-lipid association analyses simplifies genetic models, which may overlook more intricate dominant or epistatic effects that contribute to triglyceride variability[1], [2]. [3] Additionally, some SNP associations showed only equivocal replication evidence across studies, indicating that not all initial findings are robustly confirmed in independent cohorts. [4]
Variants
Section titled “Variants”Variants in genes encoding key regulators of lipid metabolism play a significant role in determining circulating levels of triglycerides, including those carried in very low-density lipoprotein (VLDL). TheGCKRgene, which encodes the glucokinase regulatory protein, influences glucose phosphorylation and hepatic triglyceride synthesis. The common variantrs1260326 within GCKRhas been strongly associated with elevated triglyceride concentrations, with one allele linked to a 10.25 mg/dl increase in triglycerides.[5] This variant’s impact on GCKRactivity affects how the liver processes glucose into fat, directly impacting VLDL production. Similarly, variants in theLPLgene, which codes for lipoprotein lipase, are crucial for triglyceride metabolism.LPL is an enzyme responsible for hydrolyzing triglycerides in chylomicrons and VLDL, allowing fatty acids to be taken up by tissues. While rs117026536 and rs10096633 are specific variants of interest in LPL and the adjacent RPL30P9 region, broader analyses of the LPLlocus consistently show strong associations with triglyceride levels, with variants likers6993414 linked to a substantial increase (14.20 mg/dl per allele) in triglyceride concentrations.[5] The LPL gene is a well-established locus impacting serum lipid levels, and its variants can lead to impaired VLDL clearance, contributing to higher circulating triglycerides. [6] Additionally, the variant rs964184 , though connected to ZPR1 (Zinc Finger Protein 1), which is generally involved in protein binding and cellular processes, is notably located near the APOA5-APOA4-APOC3-APOA1cluster, a region profoundly implicated in triglyceride metabolism. Thisrs964184 variant has been associated with an increase in triglyceride concentrations, highlighting the complex genetic architecture underlying lipid traits.[5]
The TRIB1 gene, which encodes the Tribbles Homolog 1 protein, is recognized as a key regulator in lipid metabolism, despite its exact functional mechanisms in this context still being actively investigated. Variants such as rs2954021 and rs28601761 near TRIB1 are significant due to the gene’s known influence on multiple lipid traits. For instance, other variants in the TRIB1 locus, like rs17321515 , have shown a unique pattern of association, correlating with lower triglycerides, lower LDL cholesterol, and higher HDL cholesterol, suggesting a broad impact on lipoprotein metabolism.[1] These findings underscore TRIB1’s role in influencing triglyceride-rich lipoprotein synthesis and clearance. Similarly, theMLXIPLgene, also known as ChREBP (Carbohydrate Response Element Binding Protein), acts as a critical transcription factor that activates genes involved in the synthesis of triglycerides and fatty acids in response to carbohydrate intake. Variants likers34060476 and rs13240065 in MLXIPL are pertinent, as MLXIPLis a well-established locus associated with plasma triglyceride levels.[7] Research indicates MLXIPLencodes a protein that binds and activates specific motifs in the promoters of triglyceride synthesis genes.[5]Therefore, variations in this gene can significantly alter hepatic triglyceride production, contributing to variations in VLDL triglyceride levels.
The APOE and APOC1genes are part of a cluster that encodes apolipoproteins crucial for the assembly, secretion, and catabolism of triglyceride-rich lipoproteins and cholesterol.APOE is vital for the clearance of chylomicron and VLDL remnants from circulation, while APOC1 inhibits the binding of APOE-containing lipoproteins to receptors. The variant rs584007 within the APOE - APOC1 region is associated with altered lipid profiles, particularly influencing LDL cholesterol concentrations. [5]These variations can modulate the efficiency of VLDL processing and removal, thereby impacting plasma triglyceride levels indirectly through their role in lipoprotein remnant metabolism. Another critical gene,APOB, encodes Apolipoprotein B, the primary structural protein of chylomicrons, VLDL, intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL). It is essential for the assembly and secretion of these lipoproteins. Variants inAPOB, such as rs676210 , affect both LDL cholesterol and triglyceride concentrations.[1] Alterations in APOBcan affect the number of VLDL particles released from the liver, thus directly influencing the pool of circulating triglyceride-rich lipoproteins. TheAPOBlocus is a well-replicated association for LDL cholesterol and is involved in the control of serum triglyceride levels.[8]
The LPAgene dictates the production of lipoprotein(a) or Lp(a), a plasma lipoprotein similar in structure to LDL but containing an additional apolipoprotein(a) (apo(a)) component. High Lp(a) levels are an independent risk factor for cardiovascular disease. Variants likers10455872 and rs73596816 in the LPAgene are known to be strong determinants of Lp(a) concentrations. While not directly regulating triglyceride synthesis or hydrolysis in the same way asLPL or GCKR, Lp(a) particles can interact with other lipoproteins and lipid pathways, potentially having indirect effects on triglyceride metabolism by influencing overall lipoprotein dynamics. TheLPAL2gene, or Lipoprotein A-Like 2, is structurally similar toLPA and is also involved in lipid metabolism, though its precise role is still being elucidated. The variant rs117733303 within LPAL2 warrants attention for its potential to affect lipid profiles. Given the functional similarities and proximity to LPA, variants in LPAL2may contribute to the complex regulation of lipoproteins and could indirectly impact the composition or metabolism of triglyceride-rich VLDL.
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology of Triglycerides in Very Large VLDL
Section titled “Classification, Definition, and Terminology of Triglycerides in Very Large VLDL”Characterization and Physiological Role of Triglycerides
Section titled “Characterization and Physiological Role of Triglycerides”Triglycerides are a primary type of lipid, or fat, found in the blood and serve as the main form of energy storage in the body. When energy is consumed in excess of immediate needs, it is converted into triglycerides and stored in fat cells. [5]These lipids are transported throughout the bloodstream primarily within lipoprotein particles, with very low-density lipoprotein (VLDL) being a key carrier responsible for transporting endogenously synthesized triglycerides from the liver to peripheral tissues. Elevated levels of triglycerides are a central component of dyslipidemia, a broader term for abnormal levels of lipids in the blood, which is a significant determinant of cardiovascular disease risk.[2]
Standardized Measurement and Analytical Approaches
Section titled “Standardized Measurement and Analytical Approaches”The determination of blood triglyceride concentrations typically involves measuring fasting blood samples using standard enzymatic methods.[1] A crucial operational definition in both clinical assessment and research studies is the requirement for fasting, often instructed for at least 4 hours, with mean fasting times observed around 6 ± 4 hours. [1]For genetic association analyses, triglyceride levels are frequently log-transformed to achieve a more normal distribution, and then adjusted for potential confounders such as age, age-squared, sex, diabetes status, and ancestry-informative principal components.[3] Individuals known to be on lipid-lowering therapy are generally excluded from such studies to ensure that the observed lipid concentrations reflect natural variation. [3]
Clinical Thresholds and Diagnostic Classification
Section titled “Clinical Thresholds and Diagnostic Classification”According to National Cholesterol Education Program (NCEP) guidelines, the normal range for fasting triglycerides is 30–149 mg/dl. [9]Levels exceeding this range are classified as hypertriglyceridemia, indicating an increased risk for various health conditions, particularly cardiovascular disease.[2]Very high triglyceride levels, often defined as >400 mg/dl, can also complicate the calculation of low-density lipoprotein (LDL) cholesterol using formulas like Friedewald’s, necessitating alternative measurement approaches.[1] This categorical classification helps guide clinical decisions and stratify individuals based on their metabolic risk profiles.
Genetic and Molecular Terminology
Section titled “Genetic and Molecular Terminology”Genetic studies have identified numerous loci influencing circulating triglyceride levels, contributing to the understanding of polygenic dyslipidemia.[3]Key genes consistently associated with triglyceride concentrations includeAPOA5, GCKR, LPL, TRIB1, NCAN, MLXIPL, and ANGPTL3. [5] For instance, specific SNPs near CILP2 (such as rs16996148 ) and a nonsynonymous coding SNP in the NCAN gene (rs2228603 , Pro92Ser) have shown strong associations with triglycerides. [5] Genetic association analyses typically assume an additive model of inheritance, where each copy of a risk allele contributes incrementally to the trait value, facilitating the identification of variants influencing lipid metabolism. [3]
Causes
Section titled “Causes”Polygenic Influences on VLDL Triglycerides
Section titled “Polygenic Influences on VLDL Triglycerides”The levels of triglycerides within very large VLDL particles are significantly influenced by a complex interplay of genetic factors. Research indicates that dyslipidemia, a condition encompassing elevated VLDL triglycerides, is often polygenic, meaning it arises from the cumulative effect of numerous common genetic variants, each contributing a small but measurable effect. [1] Studies have identified approximately 30 distinct genomic regions where common variants collectively increase an individual’s predisposition to various forms of dyslipidemia. [1]This polygenic architecture suggests that no single gene dictates the entire risk, but rather the combined impact of many genetic differences shapes an individual’s lipoprotein profile.
Specific Genetic Mechanisms and Pathways
Section titled “Specific Genetic Mechanisms and Pathways”Beyond the broad polygenic risk, specific genetic variants can directly impact the metabolic pathways governing triglyceride levels in VLDL. For instance, the P446L allele of theGCKR gene, identified by the variant rs1260326 , is strongly associated with increased concentrations of APOC-III. [1] APOC-IIIis a key protein synthesized in the liver that acts as an inhibitor of triglyceride catabolism, meaning it slows down the breakdown of triglycerides.[1] Elevated APOC-III levels, therefore, can lead to higher circulating triglycerides, including those carried within very large VLDL particles. Other apolipoproteins, such as APOA-I, APOB, and APOE, have also been implicated in contributing to various dyslipidemias, highlighting the intricate genetic control over lipoprotein metabolism.[1]
Biological Background
Section titled “Biological Background”The concentration of triglycerides, particularly within very low-density lipoproteins (VLDL), is a crucial aspect of lipid metabolism that significantly impacts cardiovascular health. Triglycerides are a primary form of fat stored in the body, serving as an energy reserve, and their levels are tightly regulated through complex molecular pathways. Disruptions in this regulation can lead to elevated triglyceride concentrations, contributing to conditions like coronary artery disease.[5] Understanding the intricate biological processes, from gene regulation to protein function, provides insight into how these lipid levels are maintained and what factors can lead to their imbalance.
Key Regulators of Triglyceride Metabolism
Section titled “Key Regulators of Triglyceride Metabolism”Several critical proteins and their encoding genes play central roles in governing the synthesis and overall metabolism of triglycerides. For instance, the MLXIPLgene produces a protein that actively binds to and stimulates specific regulatory regions, known as motifs, within the promoters of genes responsible for triglyceride synthesis. This direct interaction effectively increases the production of triglycerides.[5] Similarly, the ANGPTL3 protein acts as a significant regulator of lipid metabolism, influencing how the body processes fats, as demonstrated in mouse models. [5] These proteins collectively highlight the intricate molecular and cellular pathways that finely tune the body’s fat storage and utilization.
Interplay with Cholesterol Pathways
Section titled “Interplay with Cholesterol Pathways”Triglyceride metabolism is closely intertwined with cholesterol synthesis and degradation, forming a complex network of lipid regulation. The genesMVK and MMAB are critical components of these pathways, positioned adjacently in the genome and sharing a common regulatory region, or promoter. [5] The MVK gene encodes mevalonate kinase, an enzyme that catalyzes an essential early step in the biosynthesis of cholesterol, laying the groundwork for its production within cells. [5]
Genetic Mechanisms and Transcriptional Control
Section titled “Genetic Mechanisms and Transcriptional Control”Genetic factors significantly influence individual differences in lipid concentrations, including triglycerides. Studies have identified specific genetic variations, or SNPs, located near genes such as TRIB1, MLXIPL, and ANGPTL3, that are associated with varying lipid levels. [5] These genetic loci can impact the expression and function of these genes, subsequently altering metabolic processes. For example, the MLXIPLprotein exerts its influence by activating promoters of genes involved in triglyceride synthesis, demonstrating a direct genetic mechanism for controlling lipid production .
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Transcriptional and Metabolic Control of Triglyceride Synthesis
Section titled “Transcriptional and Metabolic Control of Triglyceride Synthesis”The intricate regulation of triglyceride levels, particularly within very large VLDL particles, involves precise transcriptional and metabolic control mechanisms. The protein encoded byMLXIPLplays a direct role in regulating triglyceride synthesis by binding to and activating specific motifs within the promoters of genes involved in triglyceride production.[5] This transcriptional activation is a crucial mechanism for controlling the biosynthesis of triglycerides and their subsequent packaging into very large VLDL particles, highlighting a key regulatory node in hepatic lipid metabolism that connects gene expression to circulating lipid levels.
Further intricate control over lipid metabolism involves the transcription factor SREBP2, which regulates the expression of genes such as MVK and MMAB. [5] MVK encodes mevalonate kinase, an enzyme catalyzing an early, rate-limiting step in cholesterol biosynthesis. [5] Conversely, MMAB encodes a protein that participates in a metabolic pathway responsible for cholesterol degradation. [5] The co-regulation of MVK and MMAB by SREBP2, facilitated by their shared promoter, underscores a sophisticated system for balancing cholesterol synthesis and catabolism, which indirectly impacts the overall lipid milieu relevant to triglyceride packaging.
Angiopoietin-Like Proteins in Systemic Lipid Homeostasis
Section titled “Angiopoietin-Like Proteins in Systemic Lipid Homeostasis”The angiopoietin-like protein family represents a significant class of systemic regulators influencing overall lipid metabolism. The protein homolog of ANGPTL3 is recognized as a major orchestrator of lipid processing, suggesting a conserved role in human physiology for maintaining lipid balance. [5]This protein is understood to influence the activity of lipoprotein lipase and endothelial lipase, enzymes critical for triglyceride hydrolysis and HDL metabolism, thereby impacting the levels of circulating triglycerides and their processing.
A related gene, ANGPTL4, further demonstrates the integral role of this family in lipid homeostasis, with rare variants being associated with both HDL and triglyceride concentrations in humans.[5]These proteins collectively act as crucial modulators that integrate signals across various tissues to coordinate the uptake, storage, and utilization of lipids. They play a key role in maintaining circulating triglyceride levels within a healthy range, and dysregulation of these pathways can significantly impact very large VLDL metabolism.
Post-Translational Modifications and Lipoprotein Interactions
Section titled “Post-Translational Modifications and Lipoprotein Interactions”Post-translational modifications, specifically glycosylation, represent a significant regulatory mechanism influencing lipoprotein structure and function. The geneGALNT2 encodes a widely expressed glycosyltransferase, an enzyme responsible for adding sugar moieties to proteins. [5] This enzymatic activity could potentially modify key lipoproteins, such as those forming very large VLDL, or their corresponding receptors, altering their stability, binding affinity, or clearance rates from circulation. [5]Such modifications are critical for the proper trafficking and metabolic processing of triglyceride-rich VLDL particles.
The glycosylation patterns mediated by GALNT2may therefore exert an important influence on the functional lifespan and cellular interactions of very large VLDL and other lipid-carrying particles. Alterations in these modification patterns could lead to changes in lipoprotein-receptor recognition, impacting the efficiency of triglyceride delivery to peripheral tissues and influencing overall plasma triglyceride concentrations. This mechanism highlights how subtle molecular changes can have significant systems-level consequences for lipid metabolism.
Pathway Crosstalk and Lipid Homeostasis Dysregulation
Section titled “Pathway Crosstalk and Lipid Homeostasis Dysregulation”The pathways influencing very large VLDL triglycerides are highly interconnected, demonstrating significant crosstalk at transcriptional, metabolic, and post-translational levels. For instance, while MLXIPLdirectly impacts triglyceride synthesis, its connections to broader cholesterol and lipoprotein metabolism highlight the integrated nature of lipid processing.[5] Similarly, the coordinated regulation of cholesterol synthesis (MVK) and degradation (MMAB) by SREBP2 directly influences the substrate availability for VLDL assembly and overall lipid burden. [5] The angiopoietin-like proteins (ANGPTL3, ANGPTL4) act as systemic regulators, integrating metabolic signals to fine-tune circulating lipid levels.
Dysregulation within these interconnected pathways is a critical disease-relevant mechanism contributing to altered triglyceride concentrations and an increased risk of coronary artery disease.[5] Aberrations in gene expression driven by factors like MLXIPL or SREBP2, impaired post-translational modifications by GALNT2, or systemic imbalances mediated by ANGPTL3 and ANGPTL4, can collectively lead to the accumulation of very large VLDL. Understanding these complex interactions and feedback loops, including the role of TRIB1, offers potential therapeutic targets for managing dyslipidemia and related cardiovascular complications.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Insights into Triglyceride Metabolism and Dyslipidemia
Section titled “Genetic Insights into Triglyceride Metabolism and Dyslipidemia”Genetic studies have provided significant insights into the complex polygenic nature of dyslipidemia, including the regulation of triglycerides in very low-density lipoprotein (VLDL) particles.[1] Identifying common variants across multiple loci helps to understand the underlying mechanisms that contribute to varied lipid profiles. [1] For instance, the GCKR P446L allele (rs1260326 ) is associated with increased concentrations of APOC-III, an apolipoprotein that inhibits triglyceride catabolism.[1]This specific genetic association offers a mechanistic hypothesis for elevated triglyceride levels, potentially aiding in diagnostic utility by pinpointing genetic predispositions to distinct dyslipidemic phenotypes and influencing personalized medicine approaches.[1]
Risk Assessment and Prognostic Value in Cardiometabolic Disease
Section titled “Risk Assessment and Prognostic Value in Cardiometabolic Disease”The assessment of triglycerides, particularly within very large VLDL particles, holds substantial value in comprehensive risk assessment for cardiometabolic diseases. Elevated levels can indicate an increased risk for various related conditions and complications, thereby providing important prognostic information regarding disease progression and long-term implications.[1] Understanding the genetic contributions to these specialized lipid phenotypes allows for more precise risk stratification, moving towards personalized medicine by identifying high-risk individuals based on their genetic profile and specific patterns of dyslipidemia. [1]This enables the implementation of targeted prevention strategies to mitigate adverse cardiovascular outcomes.
Guiding Treatment and Monitoring Strategies
Section titled “Guiding Treatment and Monitoring Strategies”Insights derived from the study of triglycerides in very large VLDL, alongside their genetic associations, are critical for informing treatment selection and optimizing patient care. For example, if a genetic pathway involvingAPOC-III dysregulation is implicated in an individual’s elevated triglycerides, it might suggest the potential efficacy of therapies targeting APOC-III. [1] Furthermore, routine monitoring of VLDL particle concentrations and associated apolipoproteins like APOA-I, APOB, APOC-III, and APOEis essential for tracking disease progression and evaluating the effectiveness of interventions.[1] This comprehensive monitoring strategy allows clinicians to adjust treatment regimens to improve patient outcomes and manage overlapping phenotypes effectively.
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, vol. 40, no. 2, 2008, pp. 189-197.
[2] Aulchenko, Y. S. et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, 2008.
[3] Kathiresan, S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-61.
[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] Aulchenko, YS et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 41, no. 1, 2009, pp. 47-55.
[7] Kooner, JS et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, vol. 40, no. 2, 2008, pp. 149-151.
[8] Sabatti, C et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 41, no. 1, 2009, pp. 35-46.
[9] 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. 6, 2009, pp. 1197-1205.