Phospholipids In Vldl
Phospholipids are a fundamental class of lipids that serve as primary components of biological membranes and play diverse roles in cellular function and metabolism. Within the context of human physiology, phospholipids are essential structural and functional elements of lipoproteins, such as Very Low-Density Lipoproteins (VLDL). VLDLs are lipoprotein particles synthesized by the liver, crucial for the transport of endogenous triglycerides (fats) from the liver to peripheral tissues for energy or storage. Phospholipids, particularly phosphatidylcholine (PC) and phosphatidylethanolamine (PE), form the outer monolayer of VLDL particles. This amphipathic structure allows VLDL, with its hydrophobic core of triglycerides and cholesterol esters, to circulate stably in the aqueous environment of the bloodstream.[1]The specific composition of these phospholipids can vary, including their fatty acid side chain length and degree of unsaturation (e.g., C36:4 or C36:3), and the presence of ester (diacyl) or ether (acyl-alkyl, dialkyl) bonds in their glycerol moiety.[1] This composition can influence VLDL particle stability, its interactions with enzymes like lipases, and its overall metabolic processing. Genes such as FADS1 are involved in the synthesis of phosphatidylcholine, particularly those with polyunsaturated fatty acids. [1]
Clinical Relevance
Section titled “Clinical Relevance”The concentration of circulating lipids, including those carried by VLDL, is a highly heritable trait and a significant determinant of cardiovascular disease and associated health issues.[2] Genetic variations in numerous genes involved in lipid metabolism have been consistently linked to altered levels of various lipoproteins and their components. These genes include APOB, LPL, LIPC, APOA5-APOA4-APOC3-APOA1 gene cluster, APOE-APOC1-APOC4-APOC2 gene cluster, PCSK9, and MLXIPL. [2]Specifically, genetic polymorphisms affecting phospholipid metabolism have been associated with variations in blood cholesterol levels. Moreover, they are considered potential intermediate phenotypes that may link genetic variations to complex diseases such as type 2 diabetes, bipolar disorder, and rheumatoid arthritis.[1] Investigating the genetic and metabolic factors that influence the composition and quantity of phospholipids within VLDL is therefore critical for understanding the underlying mechanisms of dyslipidemia and its wide-ranging health implications.
Public Health Importance
Section titled “Public Health Importance”Coronary artery disease and stroke are recognized as leading causes of morbidity, mortality, and disability in industrialized nations.[3]Given the strong association between lipid profiles and these prevalent conditions, research into phospholipids in VLDL carries substantial public health importance. Identifying genetic variants that affect phospholipid metabolism and VLDL characteristics can enhance the understanding of individual susceptibility to dyslipidemia and cardiovascular disease. This knowledge could facilitate the development of personalized prevention strategies, targeted therapeutic interventions, and improved diagnostic tools, ultimately contributing to better management and a reduction in the global burden of these widespread diseases.
Limitations
Section titled “Limitations”Constraints in Study Design and Statistical Power
Section titled “Constraints in Study Design and Statistical Power”Research into the genetic underpinnings of complex traits like VLDL metabolism often faces limitations inherent in large-scale genetic association studies. A primary constraint lies in the strict statistical thresholds applied to identify significant genetic variants, such as the P < 5 × 10-8 cutoff employed in some analyses. [4] While this threshold minimizes false positives, it can lead to the omission of loci with genuine, albeit smaller, effects, potentially obscuring a more complete picture of the genetic architecture influencing VLDL particle characteristics or its phospholipid content. For example, some loci with suggestive evidence, like the LPA coding SNP rs3798220 , showed associations that did not meet the prespecified stringent threshold for general dyslipidemia, despite having strong associations with related traits like lipoprotein(a) levels.[4] Such instances highlight the possibility of false negatives and indicate that the identified variants may represent only a fraction of the genetic contributors to VLDL composition and related phenotypes.
Phenotype Measurement and Generalizability
Section titled “Phenotype Measurement and Generalizability”A significant limitation in understanding the role of genetic variants in VLDL phospholipids stems from the indirect nature of the primary phenotype measurements. The studies primarily assessed “very low-density lipoprotein particle concentrations” using nuclear magnetic resonance, rather than directly quantifying the phospholipid content or composition within VLDL particles.[4] While VLDL particle concentration is a crucial metric, it offers an aggregate view and does not provide specific insights into the genetic regulation of phospholipid synthesis, transfer, or remodeling within these particles, which are distinct biological processes. Furthermore, the generalizability of findings concerning genetic influences on VLDL-related traits might be constrained by the demographic characteristics of the studied cohorts. While not explicitly detailed for the entire study population, the mention of cohorts like the Framingham Heart Study often implies a primarily European-ancestry cohort, suggesting potential limitations in applying these findings directly to other diverse populations with different genetic backgrounds and environmental exposures.
Remaining Knowledge Gaps and Complex Interactions
Section titled “Remaining Knowledge Gaps and Complex Interactions”Despite identifying common variants that contribute to dyslipidemia, a substantial portion of the heritability for VLDL-related traits, including its phospholipid content, remains unexplained, pointing to significant knowledge gaps. The identified genetic loci account for only a part of the variation, implying that numerous other genetic factors, potentially including rare variants, structural variations, or epigenetic modifications, are yet to be discovered and characterized. Moreover, the complex interplay between identified genetic predispositions and environmental factors, such as diet, lifestyle, and other physiological states, is not fully elucidated by genetic association studies focusing solely on common variants. The understanding of how these gene-environment interactions modulate VLDL phospholipid metabolism and contribute to individual differences in dyslipidemia necessitates further dedicated investigation beyond the scope of this initial genetic association analysis.
Variants
Section titled “Variants”The regulation of very-low-density lipoprotein (VLDL) and its associated phospholipids is influenced by a complex interplay of genetic variants, affecting everything from structural components to key enzymes and transcriptional regulators. Variants within or near genes encoding apolipoproteins, such as theAPOE-APOC1 cluster, the APOB gene, and the APOA5 cluster, are crucial for the assembly, secretion, and catabolism of VLDL particles. For instance, the APOE-APOC1 region, encompassing the rs1065853 variant, is well-known for its role in lipid metabolism, particularly impacting LDL cholesterol concentrations [3] which is closely linked to VLDL metabolism given that LDL is formed from VLDL. Similarly, the APOB gene, where variant rs4665710 is located, is fundamental as it encodes the primary structural protein of VLDL and chylomicrons, dictating their synthesis and interaction with cellular receptors; variants here can alter VLDL particle stability and secretion, thereby affecting its phospholipid composition. The rs964184 variant, found near the APOA5-APOA4-APOC3-APOA1 cluster (here associated with ZPR1), is strongly associated with elevated triglyceride concentrations[3] impacting VLDL content as APOA5is a potent activator of lipoprotein lipase, crucial for triglyceride hydrolysis. These variations collectively modify the overall lipid transport capacity and structural integrity of VLDL, including its phospholipid cargo.
Other variants affect the enzymatic processing and clearance of VLDL, significantly influencing phospholipid dynamics. The rs117026536 variant in the LPLgene impacts lipoprotein lipase, a critical enzyme that hydrolyzes triglycerides from VLDL and chylomicrons, facilitating the release of fatty acids and influencing VLDL remodeling.[3] Functional variations in LPL can lead to altered VLDL clearance rates and consequently affect the phospholipid-rich remnants. Meanwhile, the LPA gene, with variants such as rs10455872 and rs73596816 , encodes apolipoprotein(a), a component of lipoprotein(a), which structurally resembles LDL but carries additional apolipoprotein(a).[5]High levels of lipoprotein(a) are a risk factor for cardiovascular disease, and its metabolism can influence overall lipoprotein phospholipid exchange. Though less characterized, theLPAL2 gene, where variant rs117733303 resides, is located near LPAand may also contribute to the regulation of lipoprotein metabolism and phospholipid partitioning within VLDL and other lipoproteins.
Beyond direct structural and enzymatic roles, variants in genes that regulate lipid synthesis and transport also profoundly affect VLDL phospholipid content. The GCKR gene, with its rs1260326 variant, plays a central role in hepatic glucose metabolism by regulating glucokinase, indirectly influencingde novolipogenesis and triglyceride synthesis in the liver.[3] The T allele of rs1260326 is associated with increased triglyceride levels, suggesting enhanced VLDL production and, by extension, altered VLDL phospholipid cargo. Similarly, theMLXIPL gene, encompassing the rs34060476 variant, encodes ChREBP, a transcription factor that activates genes involved in fatty acid and triglyceride synthesis in response to dietary carbohydrates.[3]Variants here can lead to increased hepatic triglyceride synthesis and VLDL secretion, thereby increasing the overall phospholipid content of nascent VLDL particles. TheTRIB1 gene (with associated variant rs28601761 , specified as TRIB1ALin the prompt) is recognized for its strong association with triglyceride levels, influencing lipid metabolism through complex regulatory pathways.[3] Finally, DOCK7, with variant rs11207997 , has been consistently linked to serum triglyceride levels[2] contributing to the overall hepatic lipid homeostasis that dictates VLDL composition, including its phospholipid envelope.
This section cannot be generated as the provided source text does not contain specific definitions, classifications, or terminology for ‘phospholipids in VLDL’. The text mentions “very low-density lipoprotein particle concentrations” as a measured phenotype and discusses apolipoproteins such asAPOC-III in relation to lipid metabolism and dyslipidemia, but it does not define or discuss phospholipids within VLDL. Consistent with the instructions to “Do not fabricate information; rely on provided context” and “If you do not have concrete, supportable information for a paragraph or subheading, leave it out entirely,” this section must be omitted.
Key Variants
Section titled “Key Variants”Biological Background
Section titled “Biological Background”The Role of Phospholipids in Very Low-Density Lipoprotein Structure and Function
Section titled “The Role of Phospholipids in Very Low-Density Lipoprotein Structure and Function”Phospholipids are essential structural components of very low-density lipoproteins (VLDLs), playing a critical role in their formation and stability within the circulatory system. These amphipathic molecules form the outer monolayer of VLDL particles, encasing a hydrophobic core rich in triglycerides and cholesterol esters. This arrangement facilitates the solubilization and transport of these lipids, primarily synthesized in the liver, to peripheral tissues for energy storage or utilization.
The proper assembly and secretion of VLDL depend on a balanced composition of phospholipids, which are crucial for maintaining the integrity of the lipoprotein particle as it circulates through the bloodstream. This cellular function ensures efficient lipid delivery to various organs, impacting overall metabolic processes. Disruptions in the availability or composition of these structural components can affect VLDL stability, influencing lipid transport efficiency and contributing to systemic consequences related to lipid homeostasis.
Genetic Modulators of Lipid Metabolism and Phospholipid Composition
Section titled “Genetic Modulators of Lipid Metabolism and Phospholipid Composition”Genetic mechanisms significantly influence the composition and metabolism of phospholipids and other lipid components within VLDL particles. For instance, common genetic variants within the FADS1 and FADS2 gene cluster are associated with the fatty acid composition specifically in phospholipids. [6] These genes encode fatty acid desaturases, enzymes critical for the biosynthesis of polyunsaturated fatty acids, thereby directly impacting the molecular structure and diversity of phospholipids throughout the body, including those incorporated into VLDL.
Beyond phospholipid composition, other genes like ABCG5 and ABCG8(ATP binding cassette transporters) have genotypes associated with plasma lipoprotein levels, including very low-density lipoprotein, influencing the overall availability of lipids for VLDL formation and clearance.[7] Similarly, variations in ANGPTL4(angiopoietin-like 4) are known to reduce triglycerides and increase high-density lipoprotein (HDL) levels, indicating its broader role in lipid regulatory networks that indirectly affect VLDL metabolism and its phospholipid content.[8] The HNF4A (hepatocyte nuclear factor-4 alpha) gene, a transcription factor, also contains polymorphisms linked to altered beta-cell function and type 2 diabetes, suggesting its involvement in broader metabolic regulation that could encompass lipid synthesis and VLDL production. [9] These genetic influences highlight the complex interplay of gene functions and regulatory elements in shaping individual lipid profiles and susceptibility to dyslipidemia. [4]
Pathophysiological Implications of Altered Lipid and Phospholipid Homeostasis
Section titled “Pathophysiological Implications of Altered Lipid and Phospholipid Homeostasis”Disruptions in the homeostatic balance of VLDL phospholipids and overall lipid metabolism contribute to various pathophysiological processes, notably polygenic dyslipidemia. Common genetic variants identified across numerous loci collectively contribute to this condition, characterized by altered levels of circulating lipoproteins, including VLDL. [4] An imbalance in VLDL composition, potentially stemming from altered phospholipid fatty acid profiles influenced by genes like FADS1 and FADS2, can impact lipoprotein processing and clearance, contributing to systemic lipid dysregulation.
The cumulative effect of these genetic and metabolic disruptions can lead to compromised cardiovascular health, as dyslipidemia is a significant risk factor. Maintaining proper phospholipid composition within VLDL is crucial for the efficient transport of lipids and preventing their aberrant accumulation, which underscores the interconnectedness of molecular pathways, genetic predispositions, and systemic consequences in the development and progression of metabolic disorders.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Phospholipid Biosynthesis and Metabolic Interplay
Section titled “Phospholipid Biosynthesis and Metabolic Interplay”The synthesis and metabolic regulation of phospholipids, critical components of very low-density lipoproteins (VLDL), are tightly linked to the broader lipid landscape. The FADS1 gene, encoding fatty acid delta-5 desaturase, plays a significant role in the production of long-chain polyunsaturated fatty acids from essential linoleic acids, which are subsequently incorporated into glycerophospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol), including plasmalogens and plasmenogens. Genetic polymorphisms in FADS1can dramatically alter the efficiency of this desaturase reaction, impacting the cellular flux of polyunsaturated fatty acids, such as arachidonic acid (C20:4), and thus directly influencing the composition and availability of these key phospholipid species for VLDL assembly ([10]). Beyond direct phospholipid synthesis, interconnected metabolic pathways, such as cholesterol biosynthesis, contribute to the overall lipid environment influencing VLDL. For instance, genes like MVK (mevalonate kinase), which catalyzes an early step in cholesterol biosynthesis, and MMAB, involved in cholesterol degradation, are regulated by SREBP2, illustrating the coordinated control of lipid metabolism that indirectly affects VLDL phospholipid dynamics ([3]).
VLDL Assembly, Lipolysis, and Remodeling
Section titled “VLDL Assembly, Lipolysis, and Remodeling”Phospholipids are integral to the structural integrity and metabolic fate of VLDL particles. Key apolipoproteins, such as APOE, APOB, APOA5, and APOC3, are crucial for VLDL assembly, stability, and catabolism, directly influencing how phospholipids are presented on the particle surface and interact with enzymes and receptors ([3]). For example, apolipoprotein CIII (APOC3) transgenic mice exhibit a diminished VLDL fractional catabolic rate, suggesting its critical role in VLDL clearance and thus the turnover of its phospholipid components ([11]). Enzymes like hepatic lipase (LIPC) are pivotal in VLDL remodeling, affecting its phospholipid composition and overall particle metabolism; genetic variants in the LIPC promoter can lead to lower hepatic lipase activity and subsequently higher HDL cholesterol levels, which also impacts phospholipid exchange between lipoproteins ([4]). Furthermore, angiopoietin-like proteins such as ANGPTL3 and ANGPTL4regulate lipid metabolism by inhibiting lipoprotein lipase (LPL), an enzyme central to hydrolyzing triglycerides from VLDL, thereby influencing VLDL particle size and phospholipid content ([3]).
Genetic and Transcriptional Regulatory Mechanisms
Section titled “Genetic and Transcriptional Regulatory Mechanisms”The regulation of phospholipid levels in VLDL is subject to intricate genetic and transcriptional control. Transcription factors like MLXIPLbind to and activate specific motifs in the promoters of triglyceride synthesis genes, thereby orchestrating lipid flux that impacts VLDL composition, including its phospholipid layer ([3]). Beyond transcriptional activators, genetic polymorphisms in genes encoding metabolic enzymes, such as FADS1, can directly modify enzyme efficiency, profoundly altering the availability of specific polyunsaturated fatty acids for phospholipid synthesis ([10]). Post-translational modifications also contribute to regulatory complexity; for instance, GALNT2, which encodes a glycosyltransferase, could modify lipoproteins or receptors via O-linked glycosylation, potentially altering their stability, activity, or interactions within the lipid metabolic network ([3]). Even genes in cholesterol metabolism, such as HMGCR, exhibit regulatory mechanisms like alternative splicing, which can be influenced by common single nucleotide polymorphisms, highlighting the pervasive genetic influence on overall lipid homeostasis ([12]).
Systemic Lipid Network Interactions and Crosstalk
Section titled “Systemic Lipid Network Interactions and Crosstalk”The metabolism of phospholipids in VLDL does not occur in isolation but is deeply integrated into a complex network of lipid pathways, demonstrating significant crosstalk and hierarchical regulation. The interplay between triglyceride synthesis and cholesterol metabolism directly impacts VLDL composition; for example, the transcriptional regulation of triglyceride synthesis genes byMLXIPL and the cholesterol biosynthesis pathway involving MVK and MMAB are interdependent, influencing the overall lipid cargo and surface phospholipids of VLDL particles ([3]). The broader apolipoprotein family (APOA1, APOA4, APOA5, APOB, APOC1, APOC2, APOC3, APOE) contributes to the hierarchical organization of lipoprotein metabolism, where their coordinated actions dictate the formation, activity, and turnover of VLDL, consequently influencing the dynamics of its phospholipid components ([2]). The involvement of glycosyltransferases, such as GALNT2, in modifying lipoproteins or receptors further illustrates pathway crosstalk, as these modifications can alter the interaction of VLDL with other components of the lipid transport system, thereby affecting phospholipid exchange and metabolism ([3]).
Dysregulation and Disease Association
Section titled “Dysregulation and Disease Association”Dysregulation in the pathways governing VLDL phospholipids is implicated in various complex diseases, serving as crucial intermediate phenotypes linking genetic variation to pathology. A genetic polymorphism like rs4775041 , which strongly associates with phosphatidylethanolamine levels, has also shown weak associations with type 2 diabetes, bipolar disorder, and rheumatoid arthritis, suggesting that alterations in phospholipid metabolism may causally contribute to these conditions ([10]). Pathways involving MLXIPL, ANGPTL3, LPL, and LIPCare consistently associated with lipid concentrations and risk of coronary artery disease, indicating that perturbations in VLDL assembly, lipolysis, or remodeling, affecting its phospholipid constituents, contribute to dyslipidemia ([3]). For instance, an allele at rs16996148 near CILP2 and PBX4 is associated with lower concentrations of both LDL cholesterol and triglycerides, a pattern seen with APOB variants, highlighting common mechanisms of dysregulation that can be targeted therapeutically ([13]). These genetic-metabolite associations offer insights into the molecular basis of disease, providing potential therapeutic targets for intervention in conditions driven by phospholipid pathway dysregulation.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Regulation of VLDL Phospholipid Metabolism
Section titled “Genetic Regulation of VLDL Phospholipid Metabolism”Genetic variations play a crucial role in influencing the composition and metabolism of phospholipids within very low-density lipoproteins (VLDL), thereby impacting cardiovascular health. For instance, theFADS1-FADS2 gene cluster encodes desaturases that are strongly associated with the fatty acid composition in serum phospholipids, including those integrated into VLDL particles. These genetic determinants suggest a pathway for personalized medicine approaches, where an individual’s genotype could inform strategies for dietary interventions or targeted therapies to modulate VLDL phospholipid profiles and potentially mitigate dyslipidemia. Additionally, genetic variants in genes such as APOC3, which is a component of apoB-containing lipoproteins like VLDL, can impair their catabolism and hepatic uptake, directly influencing circulating VLDL levels and their associated phospholipid content, thus offering potential targets for therapeutic development. [14]
Further insights into VLDL phospholipid dynamics come from genes like PLTP (Phospholipid Transfer Protein) and LCAT (Lecithin-Cholesterol Acyltransferase). Elevated PLTPexpression has been linked to higher HDL cholesterol and lower triglycerides, indicating its role in lipoprotein remodeling, which indirectly affects VLDL phospholipid exchange and composition. Similarly,LCAT has a well-established role in lipid metabolism, using phosphatidylcholine (a key phospholipid in VLDL) as a substrate to modify lipoproteins; common variants near LCAThave been shown to influence lipid concentrations. Understanding these genetic influences on VLDL phospholipid metabolism holds prognostic value for identifying individuals at higher risk for dyslipidemia and cardiovascular disease, allowing for early risk stratification and the selection of more effective preventative or therapeutic strategies.[13]
Phospholipid Composition as Diagnostic and Prognostic Biomarkers
Section titled “Phospholipid Composition as Diagnostic and Prognostic Biomarkers”The specific composition of phospholipids within VLDL particles, including the types and saturation of their fatty acid side chains, may serve as valuable diagnostic and prognostic biomarkers in clinical practice. Advances in lipid analysis allow for the identification of detailed phospholipid structures, such as specific phosphatidylcholine (PC) types denoted by carbon chain length and number of double bonds (e.g., PC ae C33:1). Variations in these precise phospholipid profiles, influenced by genetic factors like the FADS1-FADS2 cluster, could indicate metabolic dysfunction before overt clinical symptoms appear. Such detailed compositional analysis could lead to enhanced diagnostic utility for identifying unique dyslipidemia phenotypes. [1]
Monitoring changes in VLDL phospholipid composition could also offer prognostic value, predicting disease progression or response to lipid-lowering therapies. For instance, the fatty acid profiles of serum phospholipids, which include VLDL phospholipids, are heritable traits linked to metabolic pathways. Deviations from healthy profiles may signal an increased risk for adverse cardiovascular events or help in tailoring treatment selection for specific patient subgroups. This granular insight into VLDL phospholipid makeup could move beyond traditional lipid panel measurements, enabling more personalized medicine approaches by providing a biochemical fingerprint for risk stratification and the development of targeted monitoring strategies in patients with complex dyslipidemias.
VLDL Phospholipids in Comorbidities and Cardiovascular Risk
Section titled “VLDL Phospholipids in Comorbidities and Cardiovascular Risk”Dysregulation of VLDL phospholipids is intimately linked to broader cardiometabolic comorbidities and the risk of atherosclerotic cardiovascular disease (ASCVD). VLDL-cholesterol levels, which reflect the overall burden of VLDL particles (and thus their phospholipid content), are notably associated with common comorbidities such as diabetes and hypertension, as well as lifestyle factors like smoking. Genetic loci influencing plasma triglyceride levels, such as those nearMLXIPL, TRIB1, and ANGPTL3, implicitly affect VLDL concentration and its associated phospholipid cargo, given that VLDL is the primary transporter of triglycerides. [15]
Persistent high levels of VLDL and its components contribute to atherosclerosis, a main underlying pathology for coronary artery disease (CAD) and stroke. These conditions are major causes of morbidity and mortality globally. Therefore, understanding the factors that influence VLDL phospholipid metabolism, whether genetic or environmental, provides critical insights into identifying high-risk individuals for these overlapping phenotypes and syndromic presentations. Integrated assessment of VLDL phospholipid profiles, alongside other lipid markers and genetic risk scores for traits like triglycerides, can enhance comprehensive risk stratification, inform prevention strategies, and guide early interventions to reduce the long-term implications of cardiovascular disease.[3]
References
Section titled “References”[1] Gieger, C. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, vol. 5, no. 11, 2008, e1000282. PMID: 19043545.
[2] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nature Genetics, vol. 41, no. 1, 2009, pp. 47-55.
[3] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nature Genetics, vol. 40, no. 2, 2008, pp. 161-169.
[4] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65. PMID: 19060906.
[5] Brunner, C., et al. “The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells.” J Biol Chem, vol. 271, no. 50, 1996, pp. 32403–32410.
[6] Schaeffer, L., et al. “Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.” Hum. Mol. Genet. 15 (2006): 1745–1756.
[7] Kajinami, K., et al. “ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin.”J. Lipid Res. 45 (2004): 653–656.
[8] Romeo, S., et al. “Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.” Nat. Genet. 39 (2007): 513–516.
[9] Ek, J., et al. “The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A): gene associations with type 2 diabetes or altered beta-cell function among Danes.” J. Clin. Endocrinol. Metab. 90 (2005): 3054–3059.
[10] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genetics, vol. 5, no. 1, 2009, e1000282.
[11] Aalto-Setala, K., et al. “Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.”Journal of Clinical Investigation, vol. 90, 1992, pp. 1889-1900.
[12] Burkhardt, R., et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, 2008, pp. 2071-2076.
[13] 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. PMID: 18193044.
[14] 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. 35-42.
[15] Ober, C., et al. “Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q.”J Lipid Res, vol. 50, no. 3, 2009, pp. 567-577.