Triglycerides In Very Small Vldl
Introduction
Section titled “Introduction”Triglycerides are the most common type of fat in the body, primarily stored in fat cells but also circulating in the bloodstream to provide energy. They are transported throughout the body by lipoproteins, which are complex particles composed of lipids and proteins. Very low-density lipoprotein (VLDL) particles are a key class of lipoproteins synthesized in the liver, responsible for transporting endogenous triglycerides to various tissues. The term “very small VLDL” refers to a specific subfraction of these VLDL particles, distinguished by their smaller size and density. The levels of triglycerides carried within these specific small VLDL particles can reflect distinct aspects of lipid metabolism and are increasingly recognized for their clinical implications.
Biological Basis
Section titled “Biological Basis”The production and clearance of VLDL particles, including their very small subfractions, are tightly regulated biological processes. The liver produces VLDL particles, which are then released into circulation. Enzymes such as lipoprotein lipase (LPL) and hepatic lipase play crucial roles in metabolizing VLDL triglycerides, breaking them down so fatty acids can be absorbed by tissues. Genetic variations in genes involved in lipid metabolism can significantly influence the levels of triglycerides, including those carried by very small VLDL. For instance, theAPOA5gene is known to influence triglyceride levels.[1] Similarly, variants in ANGPTL4 have been shown to reduce triglycerides, while the FADS1/FADS2 gene cluster is associated with the fatty acid composition in phospholipids, indirectly impacting lipid profiles. [2] Collectively, common genetic variants at numerous loci contribute to the polygenic nature of dyslipidemia, affecting the overall lipid profile. [3]
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of triglycerides, particularly those associated with specific lipoprotein subfractions like very small VLDL, are a significant clinical concern. High triglyceride levels are a recognized risk factor for various cardiovascular diseases, including coronary artery disease.[4]These elevated levels often form part of a broader condition known as dyslipidemia, which also includes abnormal levels of cholesterol. Understanding the precise contributions of triglycerides in very small VLDL to cardiovascular risk can aid in more refined risk stratification and personalized treatment approaches for patients. This specificity allows for a deeper insight into the pathophysiology of metabolic disorders beyond general triglyceride measurements.
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of morbidity and mortality globally, placing a substantial burden on healthcare systems and individual well-being. By elucidating the genetic and biological underpinnings that influence triglycerides in very small VLDL, researchers and clinicians can develop more effective strategies for disease prevention, early detection, and targeted interventions. This knowledge contributes to public health by informing dietary guidelines, lifestyle recommendations, and the development of novel therapeutic agents designed to modulate specific lipid subfractions. Ultimately, a better understanding of these precise lipid markers can foster advancements in personalized medicine, allowing for more tailored and preventative healthcare strategies to combat widespread cardiovascular disease.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Research into triglycerides has uncovered significant genetic associations, yet certain methodological and statistical factors warrant careful interpretation. Many analyses assume an additive model of inheritance for genotype-lipid associations, which may not fully capture complex non-additive genetic effects such as dominance or epistasis that could influence triglyceride levels.[3] Furthermore, while large meta-analyses provide power, inconsistent covariate adjustments across cohorts (e.g., age-squared in some but not all, or varying outlier exclusions) can introduce subtle biases or reduce precision. [3] The exclusion of individuals on lipid-lowering therapy, while necessary to observe genetic effects on baseline lipids, might limit the direct applicability of findings to the broader clinical population, where such treatments are common. [3]
Specific statistical challenges include the typically small effect sizes of common genetic variants, which, despite reaching genome-wide significance, explain only a modest fraction of the total variability in triglyceride levels.[5] This suggests that individually, these variants have limited predictive power for clinical classification of patients. [5] While genomic control corrections are applied to minimize confounding from population stratification, the potential for residual confounding or an inability to detect rare variants with larger effects due to insufficient sample sizes for specific genotypes (e.g., homozygous minor alleles) remains a consideration. [6] For example, lower-frequency alleles, such as a 1% frequency allele near PCSK9, may affect lipid concentrations by a larger standard deviation than common variants, yet their detection can be challenging. [3]
Generalizability and Phenotypic Heterogeneity
Section titled “Generalizability and Phenotypic Heterogeneity”A primary limitation of many studies is their predominant focus on populations of European ancestry for discovery and initial replication cohorts. [3] While some efforts extend to multi-ethnic cohorts, such as Singaporean populations, findings may not be fully generalizable to diverse global populations, limiting the transferability of genetic risk profiles across different ancestral backgrounds. [3]Phenotypic measurement protocols also exhibit variability, including differences in fasting instructions across studies, which can introduce noise and affect the comparability of triglyceride measurements.[3]
The reliance on calculated LDL cholesterol values using formulas like Friedewald’s, particularly when triglycerides are elevated (e.g., >400 mg/dL), can introduce inaccuracies or require exclusion of individuals with very high triglyceride levels, potentially biasing the sample and affecting interpretation for very small VLDL components.[3]Furthermore, the observation that some genetic loci exhibit differing impacts between males and females underscores the importance of sex-specific analyses, and that aggregated findings might obscure significant biological distinctions relevant to triglyceride metabolism.[5]
Incomplete Genetic Architecture and Environmental Influences
Section titled “Incomplete Genetic Architecture and Environmental Influences”Despite the identification of numerous genetic loci associated with triglyceride levels, a substantial portion of the heritability of this trait remains unexplained, termed “missing heritability”.[5] This suggests that current genetic models are incomplete, potentially missing interactions among genes, gene-environment interactions, or the contributions of rarer genetic variants that are not well-captured by common variant GWAS. [5] Thus, there remains substantial room for further characterization of the full genetic profiles influencing serum lipid levels. [5]
Environmental factors, such as diet, lifestyle, and other physiological states, are known to profoundly influence triglyceride levels, and while some studies adjust for basic covariates like age and sex, comprehensive accounting for the complex interplay between genetic predispositions and environmental exposures remains a significant challenge.[6] For instance, the association of a locus including FADS1-FADS2 with triglycerides, which encodes desaturases and is significant when adjusting for BMI, highlights how environmental factors can modify or confound genetic effects, pointing to a need for more nuanced gene-environment interaction studies. [6]
Variants
Section titled “Variants”Genetic variations play a crucial role in determining an individual’s lipid profile, including the levels of triglycerides, which are key components of very low-density lipoproteins (VLDL). Several single nucleotide polymorphisms (SNPs) across various genes have been identified as contributors to these lipid traits, impacting the synthesis, transport, and breakdown of fats in the body. These variants often influence the risk of dyslipidemia and associated cardiovascular conditions.
Variations in genes like GCKR, APOB, and the region involving LINC02850 and APOBare significant determinants of lipid metabolism. The glucokinase regulator gene,GCKR, produces a protein that regulates glucokinase, an enzyme critical for glucose phosphorylation, influencing both glucose and lipid metabolism. The variantrs1260326 in GCKRhas been strongly associated with elevated triglyceride concentrations, with the T allele linked to an increase of 10.25 mg/dL in triglycerides.[7] APOB(Apolipoprotein B) is a primary structural component of VLDL and low-density lipoprotein (LDL) particles, essential for their assembly and secretion. Variants such asrs2678379 in APOBcan alter the quantity or function of the APOB protein, influencing the clearance of VLDL remnants and LDL from circulation, thereby impacting circulating LDL and triglyceride levels.[3] The genomic region involving LINC02850 and APOB also hosts variant rs4564803 , which may affect APOB expression through regulatory mechanisms involving the long intergenic non-coding RNA LINC02850, thereby modulating circulating lipid levels including those found in VLDL particles.
Other crucial genes influencing triglyceride metabolism includeLPL and ALDH1A2. LPL(Lipoprotein Lipase) is an enzyme that hydrolyzes triglycerides in circulating chylomicrons and VLDL, releasing fatty acids for uptake by tissues. Variants likers115849089 and rs10096633 near LPL can impact the enzyme’s activity or expression, thus affecting the breakdown of VLDL triglycerides. [7] Dysregulation of LPLactivity can lead to higher plasma triglyceride levels and an accumulation of VLDL.ALDH1A2 (Aldehyde Dehydrogenase 1 Family Member A2) is involved in retinoid metabolism, which can indirectly influence lipid pathways. Variants such as rs1601935 and rs1077834 in or near ALDH1A2may affect this metabolic route, potentially contributing to variations in triglyceride synthesis or catabolism, though specific mechanisms linking these SNPs directly to very small VLDL triglycerides are complex and multifaceted.
Further contributing to the genetic landscape of dyslipidemia are variants associated with LIPC, APOC1, and TRIB1. LIPC (Hepatic Lipase) is an enzyme found on the surface of liver cells that plays a key role in the metabolism of HDL cholesterol and VLDL remnants. Variants like rs1077835 in LIPC can alter the enzyme’s activity, affecting the processing of triglycerides and phospholipids in lipoproteins. [3] The APOC1 (Apolipoprotein C1) gene, part of a cluster including APOEand other apolipoproteins, is involved in modulating lipoprotein metabolism, particularly by affecting the activity of LPL and the binding of lipoproteins to receptors. Variantrs157595 in the APOC1 - APOC1P1 region may impact APOC1 expression or function, influencing VLDL and LDL cholesterol levels. [7] TRIB1 (Tribbles Homolog 1) is a gene that plays a role in cellular signaling and has been implicated in regulating lipid metabolism, potentially through its effects on protein degradation. Variants like rs2954021 and rs28601761 near TRIB1are associated with significant changes in triglyceride levels, and also with LDL and HDL cholesterol.[3]
The ZPR1 gene, encoding the Zinc Finger Protein 1, is involved in diverse cellular processes, including DNA replication and transcriptional regulation, suggesting potential indirect roles in metabolic pathways. The variant rs964184 , though linked to ZPR1in some contexts, is strongly associated with triglyceride concentrations and is located near theAPOA5-APOA4-APOC3-APOA1 gene cluster. [7] The G allele of rs964184 has been shown to increase triglyceride levels by over 18 mg/dL, highlighting its significant impact on lipid profiles and, consequently, very small VLDL particle concentrations.[7]This cluster is well-known for its integral role in regulating triglyceride metabolism, whereAPOA5in particular is a key activator of lipoprotein lipase and a major determinant of plasma triglyceride levels.
Key Variants
Section titled “Key Variants”Defining Triglycerides in VLDL and Measurement Context
Section titled “Defining Triglycerides in VLDL and Measurement Context”Triglycerides are a fundamental type of fat molecule serving as the body’s primary form of energy storage and transport. These lipids are encapsulated within lipoprotein particles for circulation throughout the bloodstream, with very low-density lipoproteins (VLDL) being key carriers of triglycerides from the liver to peripheral tissues. While the specific subfraction “very small VLDL” signifies a particular size or density within the VLDL spectrum, the broader category of very low-density lipoprotein particle concentrations is precisely measured using advanced techniques such as nuclear magnetic resonance[3]. Understanding the levels of triglycerides carried by these VLDL particles, including very small VLDL, is crucial for assessing lipid metabolism and potential cardiovascular risk.
Lipoprotein Classification and Related Terminology
Section titled “Lipoprotein Classification and Related Terminology”The classification of lipoproteins is a structured system based on their density, composition, and electrophoretic mobility, facilitating the categorization of different lipid profiles. Key lipoprotein classes include high-density (HDL), low-density (LDL), intermediate-density (IDL), and very low-density (VLDL) lipoprotein particles[3]. Each class plays a distinct role in lipid transport, with VLDL primarily responsible for delivering endogenous triglycerides. Additionally, the term “remnant lipoprotein” refers to partially metabolized triglyceride-rich lipoproteins, which also comprise a distinct and measurable phenotype with associated cholesterol and triglyceride content[3]. This detailed nomenclature allows for the differentiation of various lipoprotein species, including subfractions that may carry triglycerides in specific forms like very small VLDL.
Biochemical Modulators of Triglyceride Levels
Section titled “Biochemical Modulators of Triglyceride Levels”The regulation of triglyceride metabolism within lipoproteins is a complex process influenced by various genetic and biochemical factors. Apolipoprotein C-III (APOC-III), for instance, is a critical protein synthesized in the liver that acts as an inhibitor of triglyceride catabolism, thereby affecting the clearance of triglyceride-rich lipoproteins[3]. Variations in genes like GCKR have been shown to impact APOC-III levels; specifically, the GCKR P446L allele (rs1260326 ) is associated with increased concentrations of APOC-III [3]. Such genetic associations highlight mechanistic pathways through which common variants contribute to polygenic dyslipidemia, influencing the levels of triglycerides in various lipoprotein particles, including very small VLDL.
Causes of Triglycerides in Very Small VLDL
Section titled “Causes of Triglycerides in Very Small VLDL”Genetic Predisposition and Polygenic Influences
Section titled “Genetic Predisposition and Polygenic Influences”The concentration of triglycerides within very small VLDL particles is significantly shaped by an individual’s genetic architecture. Studies indicate that common genetic variants found at approximately 30 loci collectively contribute to a polygenic dyslipidemia, influencing various facets of lipid metabolism, including specific VLDL triglyceride levels . This protein directly binds to and activates specific DNA motifs located in the promoter regions of genes involved in triglyceride production, thereby influencing their expression and subsequent lipid output.[7] Furthermore, the ANGPTL3gene, a major regulator of lipid metabolism, especially in mouse models, also impacts triglyceride concentrations.[7] Related to this, rare genetic variants in ANGPTL4have been linked to significant changes in both high-density lipoprotein (HDL) and triglyceride concentrations in humans, highlighting a broader family of proteins that govern lipid homeostasis and the breakdown of lipoproteins.[7] These genes collectively illustrate how genetic variations can alter key biomolecules and metabolic processes, leading to changes in systemic lipid profiles.
Coordinated Control of Cholesterol Biosynthesis and Degradation
Section titled “Coordinated Control of Cholesterol Biosynthesis and Degradation”Cholesterol metabolism is intrinsically linked to triglyceride dynamics, and several genes contribute to this interplay. TheMVK gene encodes mevalonate kinase, an enzyme critical for catalyzing an early step in the mevalonate pathway, which is the primary route for cholesterol biosynthesis. [7] Adjacent to MVK, the MMAB gene encodes a protein involved in a metabolic pathway responsible for cholesterol degradation. [7] Both MVK and MMAB are transcriptionally regulated by SREBP2 (Sterol Regulatory Element-Binding Protein 2), a master transcription factor that senses cellular cholesterol levels and modulates the expression of genes involved in cholesterol synthesis and uptake. [7]These genes share a common promoter region, suggesting a coordinated genetic mechanism to maintain cholesterol balance, and through this, influence overall lipid homeostasis and very small VLDL triglyceride levels.
Post-translational Modification of Lipoproteins
Section titled “Post-translational Modification of Lipoproteins”Beyond direct synthesis and breakdown, the functionality and clearance of lipoproteins can be influenced by post-translational modifications. The GALNT2 gene, which encodes a widely expressed glycosyltransferase, is a potential contributor to these modifications. [7] Glycosyltransferases are enzymes that add sugar molecules to proteins or lipids, and in the context of lipid metabolism, GALNT2 could potentially modify the structure of lipoproteins themselves or their corresponding receptors. [7]Such modifications can alter lipoprotein stability, binding affinity to receptors, or rates of clearance from circulation, thereby influencing the systemic concentrations of various lipid species, including triglycerides in very small VLDL particles. These cellular functions demonstrate another layer of regulatory complexity in lipid metabolism.
Systemic Effects and Homeostatic Balance in Lipid Metabolism
Section titled “Systemic Effects and Homeostatic Balance in Lipid Metabolism”The integrated actions of these genes and their products contribute to the complex regulation of lipid concentrations throughout the body. Disruptions in the molecular and cellular pathways controlled by MLXIPL, ANGPTL3, ANGPTL4, MVK, MMAB, SREBP2, and GALNT2 can lead to significant homeostatic imbalances. For instance, altered activity of MLXIPLcan directly impact hepatic triglyceride output, affecting VLDL assembly and secretion. Similarly, variations inANGPTL3 and ANGPTL4can modify the systemic processing and clearance of triglyceride-rich lipoproteins. The intricate balance between cholesterol synthesis and degradation orchestrated byMVK, MMAB, and SREBP2also indirectly influences the availability of lipids for VLDL formation. Collectively, these genetic and molecular mechanisms underscore how precise control at the gene, enzyme, and protein level is essential for maintaining healthy triglyceride levels and preventing pathophysiological processes associated with lipid dysregulation.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Biosynthesis and Secretion of Triglyceride-Rich Lipoproteins
Section titled “Biosynthesis and Secretion of Triglyceride-Rich Lipoproteins”The formation and release of triglycerides (TG) within very low-density lipoproteins (VLDL) are intricate metabolic processes governed by a network of genes and their regulatory elements. Key among these is the transcription factor encoded by MLXIPL, which binds to and activates specific motifs in the promoters of genes essential for triglyceride synthesis, directly influencing the cellular capacity for lipid production and packaging into VLDL particles.[7] Cholesterol biosynthesis, an essential pathway providing structural components for VLDL, is also tightly linked, with genes such as MVK (mevalonate kinase) catalyzing early steps in this pathway, regulated by transcription factors like SREBP2. [7] Furthermore, the FADS1 and FADS2 gene clusters play a crucial role by encoding fatty acid desaturases, enzymes that regulate the desaturation of fatty acids through the introduction of double bonds, thereby influencing the composition and potential stability of the triglycerides incorporated into VLDL. [5] These interconnected biosynthetic pathways ensure the continuous supply and proper assembly of triglycerides and associated lipids for secretion as nascent VLDL.
Lipolytic Processing and Clearance of VLDL
Section titled “Lipolytic Processing and Clearance of VLDL”Once secreted, VLDL particles undergo enzymatic processing and clearance from circulation, a critical phase for managing systemic triglyceride levels. This catabolism is primarily mediated by lipoprotein lipase (LPL), an enzyme that hydrolyzes triglycerides within VLDL, releasing fatty acids for tissue uptake. [7] The activity of LPL is intricately regulated by various factors, including apolipoproteins like APOCIII, which can inhibit LPL function, and APOE, which acts as a ligand for receptor-mediated clearance of VLDL remnants. [3] Another significant regulator is angiopoietin-like protein 4 (ANGPTL4), identified as a potent inhibitor of LPL, thereby contributing to hypertriglyceridemia. [3] Furthermore, the protein Sortilin/neurotensin receptor-3 has been shown to bind and mediate the degradation of LPL, highlighting another layer of post-translational control over this crucial lipolytic enzyme. [7]
Transcriptional and Post-Translational Control of Lipid Metabolism
Section titled “Transcriptional and Post-Translational Control of Lipid Metabolism”The precise regulation of triglyceride metabolism involves sophisticated transcriptional and post-translational mechanisms that fine-tune protein expression and activity. BeyondMLXIPL’s direct transcriptional activation of triglyceride synthesis genes, other regulatory nodes exist, such as the G-protein–coupled receptor-induced protein encoded byTRIB1, which is implicated in the regulation of mitogen-activated protein kinases (MAPK) and may influence lipid metabolism through this signaling pathway. [7] Post-translational modifications, like O-linked glycosylation, represent another vital regulatory layer, with enzymes such as polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2) mediating the transfer of N-acetylgalactosamine to proteins, potentially modifying lipoproteins or receptors involved in HDL cholesterol and triglyceride metabolism.[3] Genes like GCKR(glucokinase regulatory protein) also show strong associations with triglyceride levels, suggesting their involvement in metabolic flux control related to glucose and lipid homeostasis.[8]
Integrated Regulatory Networks and Dyslipidemia
Section titled “Integrated Regulatory Networks and Dyslipidemia”The regulation of triglyceride levels within VLDL is not isolated but is part of a complex, integrated network where various pathways crosstalk and contribute to overall lipid homeostasis. Genetic studies have illuminated several loci where variants concurrently influence multiple lipid traits, such as those nearTRIB1 (rs17321515 ), which are associated with lower triglycerides, lower LDL cholesterol, and higher HDL cholesterol, demonstrating coordinated regulation across lipoprotein classes.[3] These genomic insights reveal a polygenic architecture for dyslipidemia, where combinations of common variants in genes like ABCA1, APOB, CETP, LPL, LDLR, and numerous apolipoprotein gene clusters (APOA5-APOA4-APOC3-APOA1 and APOE-APOC1-APOC4-APOC2) contribute to the overall variation in lipid concentrations. [5]Dysregulation within these interconnected pathways, whether through specific gene variants or environmental factors, can lead to emergent properties like hypertriglyceridemia, increasing the risk for cardiovascular events, even in non-fasting states.[9]
Clinical Relevance
Section titled “Clinical Relevance”Genetic Underpinnings of Triglyceride Metabolism and Risk Assessment
Section titled “Genetic Underpinnings of Triglyceride Metabolism and Risk Assessment”Genetic studies have significantly advanced our understanding of triglyceride regulation and its implications for cardiovascular health. Multiple genetic loci have been identified as influencing triglyceride concentrations, often in conjunction with other lipid traits like HDL and LDL cholesterol[3]. [7]For instance, specific single nucleotide polymorphisms (SNPs) such asrs4846914 in GALNT2 are associated with higher triglycerides and lower HDL, while rs17145738 near TBL2 and MLXIPL shows the opposite pattern. [3] These genetic insights can serve as valuable tools for identifying individuals predisposed to dyslipidemia and for refining risk assessment beyond traditional lipid panels.
Further research has revealed complex genetic associations, such as rs17321515 near TRIB1, which is linked to lower triglycerides, lower LDL cholesterol, and higher HDL cholesterol—a unique pattern among lipid-modulating SNPs. [3] Similarly, rs16996148 near CILP2 and PBX4 is associated with lower levels of both LDL cholesterol and triglycerides. [3]These findings highlight the polygenic nature of dyslipidemia, where common variants at multiple loci collectively influence lipid phenotypes and contribute to an individual’s overall lipid profile and associated disease risk[3]. [3]
Triglycerides as a Prognostic and Diagnostic Biomarker
Section titled “Triglycerides as a Prognostic and Diagnostic Biomarker”Triglyceride levels hold significant prognostic value in predicting health outcomes and disease progression, particularly concerning cardiovascular health. Research indicates that even non-fasting triglyceride levels are associated with an increased risk of cardiovascular events, underscoring their relevance in common physiological states.[9]The measurement of triglycerides is a standard component of lipid panels, and deviations from healthy ranges are routinely used in clinical practice for diagnostic utility and to identify individuals at increased risk for metabolic disorders and coronary heart disease.[3]
The intricate associations between triglycerides and other lipid components, such as HDL and LDL cholesterol, underscore the importance of evaluating triglycerides within a broader lipid context. Genetic variants influencing triglycerides often exhibit pleiotropic effects, simultaneously impacting HDL and LDL levels, which can provide clues into underlying lipoprotein metabolism pathways.[3] For instance, the FADS1-FADS2locus is associated with fatty acid composition in serum phospholipids and LDL, further linking triglyceride metabolism to broader lipid-related health risks.[10]
Personalized Risk Stratification and Therapeutic Guidance
Section titled “Personalized Risk Stratification and Therapeutic Guidance”Integrating genetic information with conventional clinical risk factors offers a powerful approach to personalized risk stratification for conditions like coronary heart disease (CHD). Genetic risk scores, constructed from multiple lipid-associated loci, have demonstrated explanatory value in predicting lipid levels, including triglycerides, and can improve CHD risk classification when added to traditional factors such as age, BMI, sex, and existing lipid values.[11] This enhanced stratification allows for the identification of high-risk individuals who might benefit from earlier or more intensive prevention strategies.
Understanding the specific genetic drivers of triglyceride levels can also inform treatment selection and monitoring strategies. For example, the unique lipid-modulating patterns associated with certain SNPs may offer insights into tailored therapeutic approaches targeting specific pathways of lipid metabolism.[3]While studies often exclude individuals on lipid-lowering therapy to isolate genetic effects, the recognition that these therapies significantly impact triglyceride levels underscores the clinical utility of monitoring triglycerides for assessing treatment response and guiding ongoing patient care.[3]
References
Section titled “References”[1] Pennacchio, L. A. et al. “An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.” Science, 2001.
[2] Romeo, S. et al. “Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.” Nature Genetics, 2007.
[3] Kathiresan, S. et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2008, pp. 56-65.
[4] Sarwar, N. et al. “Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.”Lancet, 2010.
[5] Aulchenko, Y. S. 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.
[6] 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.
[7] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-69.
[8] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, vol. 4, no. 11, 2008, e1000282.
[9] Wallace, C. et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139-49.
[10] 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, 2008, pp. 32-46.
[11] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 12, 2008, pp. 1481-1488.