Triglycerides In Very Large Hdl
Introduction
Section titled “Introduction”High-density lipoprotein (HDL) cholesterol is a crucial component of lipid metabolism, often referred to as “good cholesterol” due to its role in reverse cholesterol transport, where it helps remove excess cholesterol from cells and transport it back to the liver for excretion.[1]HDL is not a single entity but a heterogeneous group of particles varying in size, density, and lipid and protein composition. Among these, very large HDL particles represent a specific subfraction that can carry various lipids, including triglycerides. Triglycerides are a type of fat found in the blood, serving as a major energy source, and their levels are closely monitored as indicators of cardiovascular health.[2] The presence and concentration of triglycerides within very large HDL particles reflect the dynamic interplay of lipid synthesis, transport, and catabolism.
Biological Basis
Section titled “Biological Basis”The metabolism of HDL particles, including their triglyceride content, is a complex process involving numerous enzymes and proteins. Key enzymes such as lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) play significant roles in modulating the lipid composition of HDL. LPLis crucial for the hydrolysis of triglycerides in triglyceride-rich lipoproteins, impacting the transfer of triglycerides to HDL and their subsequent processing.[2] CETPfacilitates the exchange of triglycerides from very low-density lipoproteins (VLDL) for cholesteryl esters in HDL, a process that can lead to triglyceride enrichment of HDL particles.[2] LCAT esterifies cholesterol on HDL, which is essential for HDL maturation. Genetic variations in genes encoding these proteins, such as LPL (rs10468017 , rs2083637 ), CETP (rs12678919 ), LIPC (rs10468017 ), LIPG (rs10401969 ), and the APOA5cluster, have been strongly associated with variations in HDL cholesterol and triglyceride levels, influencing the overall lipid profile.[2] These genetic associations highlight the intricate pathways that determine the quantity of triglycerides within different HDL subfractions.
Clinical Relevance
Section titled “Clinical Relevance”Elevated triglyceride levels in the blood, often in conjunction with low HDL cholesterol, are hallmarks of dyslipidemia, a condition strongly linked to an increased risk of cardiovascular disease (CVD).[1]While high HDL cholesterol generally correlates with reduced CVD risk, the functionality of HDL, particularly its capacity for reverse cholesterol transport, can be impaired when it becomes enriched with triglycerides. Triglyceride-rich HDL particles may be more susceptible to catabolism, leading to lower overall HDL levels and potentially reduced protective effects. Genetic studies have identified numerous loci that contribute to dyslipidemia, including those affecting triglyceride and HDL concentrations.[3]Understanding the specific composition of HDL subfractions, such as the triglyceride content in very large HDL, may provide more refined insights into an individual’s cardiovascular risk beyond traditional fasting lipid measurements.[4]
Social Importance
Section titled “Social Importance”The prevalence of dyslipidemia and cardiovascular disease worldwide underscores the social importance of understanding lipid metabolism in detail. Identifying genetic predispositions to specific lipid profiles, such as increased triglycerides in very large HDL, can aid in personalized risk assessment and targeted interventions. Public health initiatives focused on lifestyle modifications (diet and exercise) and pharmacological treatments (lipid-lowering therapies) are crucial in managing dyslipidemia. Research into genetic variations influencing these traits contributes to a more comprehensive understanding of disease etiology and can lead to the development of novel diagnostic tools and therapeutic strategies. Ultimately, a deeper understanding of the genetic and environmental factors that govern triglyceride levels in HDL aims to reduce the burden of cardiovascular disease on individuals and healthcare systems globally.
Limitations
Section titled “Limitations”Limitations in Study Design and Phenotype Characterization
Section titled “Limitations in Study Design and Phenotype Characterization”The studies primarily relied on an additive model of inheritance for genotype-lipid association analyses, which might not fully capture more complex genetic interactions like dominance or epistasis, potentially overlooking additional influential variants. While efforts were made to standardize analyses, inconsistencies existed, such as one replication cohort not adjusting for age-squared, introducing subtle variations in statistical modeling across studies. The use of fixed-effects meta-analysis, although robust, might also be sensitive to unacknowledged heterogeneity between cohorts, despite attempts to assess it. [3]
Phenotype characterization also presented limitations; for instance, while most cohorts required fasting, one study reported a broader fasting time range (mean 6 ± 4 hours), which could contribute to variability in triglyceride measurements. The calculation of LDL cholesterol using Friedewald’s formula meant that individuals with triglyceride levels exceeding 400 mg/dl had missing LDL values, potentially biasing analyses in this high-risk subgroup. Furthermore, the exclusion of extreme outliers in some cohorts, though a common practice, could reduce the generalizability of findings to the entire population, especially for individuals at the ends of the lipid distribution.[3]
Constraints on Generalizability and Population Representativeness
Section titled “Constraints on Generalizability and Population Representativeness”A significant limitation regarding generalizability stems from the predominant focus on populations of European ancestry across the discovery and replication cohorts. Efforts were made to identify and exclude individuals of non-European ancestry in some analyses, which restricts the direct applicability of these findings to a broader global population. The genetic architecture and frequency of variants influencing lipid levels can differ substantially across diverse ancestral backgrounds, suggesting that the identified associations may not hold true or have the same effect size in other ethnic groups.[3]
The ascertainment of study cohorts also introduces potential biases, as some genome-wide association studies have historically included individuals selected based on the presence or absence of specific diseases like diabetes. Such ascertainment can distort the estimation of population-level impact and the detection of associations, even if some of the presented analyses aimed for population-based sampling. Furthermore, the observation of sex-specific effects for certain loci on lipid levels, such as LPL influencing HDL cholesterol differently in males and females, highlights that analyses combining sexes might mask or underappreciate critical biological distinctions and require further stratified investigation. [1]
Unaccounted Genetic and Environmental Influences
Section titled “Unaccounted Genetic and Environmental Influences”A prominent limitation is the substantial proportion of unexplained variability, or “missing heritability,” for triglyceride levels and other lipid traits. The common variants identified across these large-scale studies collectively explain only a modest fraction of the total phenotypic variance—for instance, 7.4% for triglycerides and 6% of total variability in one study. This suggests that a significant portion of genetic influence on lipid concentrations remains undiscovered, likely attributable to rare variants, more complex genetic architectures such as epistatic interactions, or structural variants not well-captured by common SNP arrays.[3]
Beyond purely genetic factors, the research also faced limitations in fully accounting for environmental or gene-environment confounders. While basic adjustments were made for factors like age and sex, and in some cases for diabetes status or BMI, the comprehensive interplay of lifestyle, dietary habits, and other environmental exposures with genetic predispositions to affect lipid metabolism was not exhaustively modeled. This gap means that potential gene-environment interactions, which could significantly modify genetic effects on triglyceride levels, are largely uncharacterized, representing a considerable area for future investigation to enhance our understanding of lipid regulation.[2]
Variants
Section titled “Variants”Genetic variations at several loci contribute to the complex regulation of lipid metabolism, including the levels of triglycerides carried within very large high-density lipoprotein (HDL) particles. Understanding these variants helps to clarify pathways involved in cardiovascular health. These associations are critical for deciphering the genetic architecture of dyslipidemia and identifying individuals at risk for related conditions.
Variants impacting triglyceride synthesis and catabolism include those nearLPL, GCKR, TRIB1AL, and ZPR1. The lipoprotein lipase (LPL) gene is crucial for hydrolyzing triglycerides in chylomicrons and very low-density lipoproteins (VLDL), releasing fatty acids for tissue uptake. Variants like rs10096633 located near LPLcan influence this enzymatic activity, thereby affecting circulating triglyceride levels and, by extension, the triglyceride content of HDL particles.[3] For instance, variants in the LPL locus, such as rs6993414 and rs894210 , have been significantly associated with altered triglyceride concentrations, where specific alleles can lead to an increase in triglyceride levels.[2]Similarly, the glucokinase regulatory protein (GCKR) gene plays a central role in regulating glucose metabolism and hepatic triglyceride synthesis. The common variantrs1260326 in GCKRis a strong determinant of triglyceride levels, with the T allele linked to increased concentrations.[2] This variant, along with rs780093 , influences the activity of glucokinase, indirectly affecting the supply of glycerol-3-phosphate for triglyceride production in the liver. TheTRIB1AL gene (Tribbles Homolog 1) and its associated variants rs28601761 and rs2954021 are also implicated in triglyceride regulation, potentially through effects on hepatic lipid metabolism and VLDL assembly and secretion.[3] Variants near TRIB1have been identified as significant contributors to triglyceride levels.[2] Additionally, the variant rs964184 in ZPR1(Zinc Finger Protein, Recombinant 1) is significantly associated with triglyceride concentrations, and notably, it is located near theAPOA5-APOA4-APOC3-APOA1 gene cluster, which is a well-established region for lipid metabolism. [2] While ZPR1is involved in cell proliferation and survival, its close proximity to key lipid genes suggests a potential indirect influence on triglyceride metabolism.
Other variants affect the remodeling and composition of HDL particles, which can influence their triglyceride content. The cholesteryl ester transfer protein (CETP) gene, which includes variants like rs17231506 and rs3764261 , encodes a protein that facilitates the exchange of cholesteryl esters and triglycerides between lipoproteins, primarily between HDL and VLDL/LDL. [1] Functionally, increased CETPactivity typically leads to lower HDL cholesterol and higher triglyceride-rich HDL, by transferring triglycerides from VLDL to HDL in exchange for cholesteryl esters. Indeed, variants in theCETP locus, such as rs12678919 and rs289714 , are strongly associated with altered HDL cholesterol levels. [2] Similarly, the hepatic lipase (LIPC) gene, affected by variants like rs11632618 , encodes an enzyme that hydrolyzes triglycerides and phospholipids in HDL, contributing to its maturation and catabolism.[2] Variants in LIPCare consistently associated with HDL cholesterol concentrations. The ATP-binding cassette transporter A1 (ABCA1) gene, with variants such as rs2575876 , rs2740488 , and rs11789603 , is critical for the initial step of HDL formation by mediating cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I. [1] Alterations in ABCA1function can lead to reduced HDL levels and impact the overall capacity for reverse cholesterol transport, influencing the lipid exchange dynamics that govern triglyceride content in HDL particles.
Further variants contribute to lipid metabolism through broader cellular and metabolic processes. The aldehyde dehydrogenase 1 family member A2 (ALDH1A2) gene, housing variants like rs1601933 , rs4775033 , rs1318175 , and rs11632618 (also associated with LIPC), is involved in retinoid acid metabolism, a pathway with diverse regulatory roles, including influences on adipogenesis and lipid homeostasis. [2]While not directly related to lipid transfer proteins, changes in retinoid signaling can indirectly impact pathways that modulate triglyceride synthesis or breakdown, potentially affecting their presence in HDL. Variants inPCIF1 (rs6073958 ), which encodes a PCIF1-like protein involved in RNA processing, and HERPUD1 (rs17231506 , rs3764261 ), involved in ER stress response and protein degradation, are also implicated. [3] Although their direct mechanisms on very large HDL triglycerides are less understood, they may influence overall cellular health and gene expression patterns that indirectly modulate lipid metabolism. The RPL30P9 gene (rs10096633 ), a ribosomal protein pseudogene located near LPL, suggests complex regulatory interplay where genetic variations can have pleiotropic effects on both protein synthesis machinery and adjacent lipid-related genes. [2]
Key Variants
Section titled “Key Variants”Definition and Composition of Lipoprotein Lipids
Section titled “Definition and Composition of Lipoprotein Lipids”The trait “triglycerides in very large HDL” refers to a specific measure of lipid content within a particular subfraction of high-density lipoprotein (HDL) particles. Triglycerides are a type of lipid, representing the main form of fat stored in the body and transported in the blood. High-density lipoprotein (HDL) cholesterol, often termed “good cholesterol,” is a component of HDL particles, which play a critical role in reverse cholesterol transport from peripheral tissues back to the liver.[5]While this trait pinpoints triglycerides within a distinct, large HDL subtype, its foundational understanding relies on the broader definitions and metabolic roles of both triglycerides and HDL cholesterol within the complex system of blood lipoproteins, which also include low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) cholesterol.[5]
Measurement and Operational Criteria
Section titled “Measurement and Operational Criteria”The precise quantification of “triglycerides in very large HDL” would involve specific lipoprotein fractionation techniques, but the general measurement principles for triglycerides and HDL cholesterol are well-established. For research and clinical purposes, blood lipid concentrations, including triglycerides and HDL cholesterol, are typically determined from fasting blood samples.[3] Fasting durations of at least 4 hours, often with a mean around 6 hours, are commonly observed. [3] Standard enzymatic methods are employed to measure these lipid concentrations. [3]In genetic association studies, triglyceride values are frequently log-transformed to achieve a more normal distribution for statistical analyses.[3] Further adjustments for covariates such as age, age squared, sex, diabetes status, and ancestry-informative principal components are often performed to derive “residual lipid concentrations,” which serve as the phenotypes for genotype-phenotype association analyses, particularly when excluding individuals on lipid-lowering therapy. [3]
Clinical Classification and Dyslipidemia Terminology
Section titled “Clinical Classification and Dyslipidemia Terminology”The clinical significance of lipid levels, including triglycerides and HDL cholesterol, is largely understood through their association with cardiovascular disease risk. According to National Cholesterol Education Program (NCEP) guidelines, normal ranges for triglycerides are typically 30–149 mg/dl, and for HDL-cholesterol, 40–80 mg/dl.[5] Deviations from these ranges contribute to a condition known as dyslipidemia, which broadly refers to abnormal levels of lipids in the blood. [3]The trait “triglycerides in very large HDL” would contribute to a more nuanced classification of dyslipidemia, offering insights beyond total triglyceride and HDL cholesterol levels. Dyslipidemia is often polygenic, meaning multiple genetic loci contribute to an individual’s lipid profile and risk.[3] Specific genes, such as GCKR, TRIB1, MLXIPL, NCAN, and ANGPTL3, have been associated with triglyceride levels, whileMMAB-MVK and GALNT2 are linked to HDL cholesterol. [3]These genetic insights refine our understanding of lipid metabolism and disease predisposition.
Biological Background
Section titled “Biological Background”Regulation of Triglyceride Synthesis and Metabolism
Section titled “Regulation of Triglyceride Synthesis and Metabolism”The concentration of triglycerides, including those associated with very large high-density lipoprotein (HDL), is critically influenced by a network of genetic and molecular pathways that govern their synthesis and breakdown. For instance, theMLXIPLgene encodes a protein that plays a direct role in activating specific DNA motifs found in the promoters of genes responsible for triglyceride synthesis. This activation leads to increased production of triglycerides, thereby affecting their overall levels in the bloodstream and within lipoprotein particles[2] Another key regulator is the ANGPTL3 gene, whose protein product is recognized as a major controller of lipid metabolism in animal models. Furthermore, a related gene, ANGPTL4, has rare variants that are associated with varying concentrations of both HDL and triglycerides in humans, underscoring the interconnectedness of these lipid components [2]These genes illustrate how precise molecular mechanisms contribute to the dynamic balance of triglyceride metabolism, directly impacting their presence in various lipoprotein fractions.
Interplay with Cholesterol Biosynthesis and Degradation
Section titled “Interplay with Cholesterol Biosynthesis and Degradation”Triglyceride metabolism is intricately linked with pathways involved in cholesterol biosynthesis and degradation. Two neighboring genes,MVK and MMAB, exemplify this connection, as they are co-regulated by the transcription factor SREBP2 and share a common promoter region [2] The MVK gene is responsible for encoding mevalonate kinase, an enzyme crucial for catalyzing an early, rate-limiting step in the complex cholesterol biosynthesis pathway. Conversely, the MMAB gene encodes a protein that participates in a separate metabolic pathway dedicated to the degradation of cholesterol [2]This dual regulation highlights a coordinated cellular response to maintain lipid homeostasis, where the production and removal of cholesterol directly influence, and are influenced by, triglyceride levels and overall lipoprotein profiles.
Genetic Control of Lipid Homeostasis
Section titled “Genetic Control of Lipid Homeostasis”The genetic landscape significantly dictates an individual’s lipid concentrations, including triglycerides. Variations located near genes such as TRIB1, MLXIPL, and ANGPTL3have been identified as influential factors impacting triglyceride levels[2] These genetic loci, through their encoded proteins, establish critical regulatory nodes within the broader lipid metabolic network. The shared regulatory mechanisms, such as SREBP2’s control over genes like MVK and MMAB, demonstrate how coordinated gene expression contributes to maintaining the delicate balance of lipids in the body [2] Such genetic influences ultimately shape the concentrations of triglycerides and HDL, with potential systemic consequences for health.
Potential Modulatory Roles and Systemic Health Implications
Section titled “Potential Modulatory Roles and Systemic Health Implications”Beyond directly recognized metabolic enzymes, other biomolecules may play modulatory roles in lipid metabolism. For instance, the GALNT2 gene encodes a widely expressed glycosyltransferase, an enzyme capable of modifying proteins or receptors through the addition of sugar molecules [2]Such modifications could potentially alter the function or stability of lipoproteins, like HDL, or their interacting receptors, thereby indirectly influencing triglyceride levels. The comprehensive regulation of lipid concentrations is particularly relevant due to their strong association with the risk of coronary artery disease[2]Therefore, understanding these diverse molecular and genetic underpinnings is crucial for deciphering the full biological context of triglycerides in very large HDL and their broader impact on human health.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Regulation of Triglyceride and HDL Dynamics
Section titled “Metabolic Regulation of Triglyceride and HDL Dynamics”The concentration of triglycerides within very large HDL particles is intricately governed by key metabolic regulators, notably the angiopoietin-like proteins. For instance, ANGPTL3plays a significant role in overall lipid metabolism, and its actions can influence the distribution and catabolism of triglycerides across various lipoprotein classes.[6] Similarly, variations in ANGPTL4have been directly associated with a reduction in plasma triglyceride levels and a concomitant increase in HDL concentrations, suggesting a crucial role in lipid partitioning and lipoprotein remodeling. These proteins modulate the activity of lipolytic enzymes, thereby controlling the breakdown and clearance of triglyceride-rich lipoproteins and the subsequent remodeling of HDL particles.[7]
Transcriptional Control of Lipid Homeostasis
Section titled “Transcriptional Control of Lipid Homeostasis”Beyond direct enzyme regulation, the cellular machinery governing lipid synthesis and transport is under precise transcriptional control. The sterol regulatory element-binding proteins (SREBPs) are central to this regulation, acting as master transcription factors. Specifically, SREBP-2 is known to regulate gene expression involved in various metabolic pathways, including those linked to isoprenoid and adenosylcobalamin metabolism. [8]This transcriptional network ensures coordinated biosynthesis and feedback regulation, influencing the availability of lipid precursors and the overall lipid profile, which can indirectly impact the composition of HDL particles, including their triglyceride content.
Intracellular Signaling and Lipid Modifiers
Section titled “Intracellular Signaling and Lipid Modifiers”Intracellular signaling cascades provide another layer of regulation for lipid metabolism, integrating various external stimuli with cellular responses. The human tribbles protein family exemplifies this, controlling mitogen-activated protein kinase (MAPK) cascades. [9]These MAPK pathways are fundamental signaling modules involved in cell growth, proliferation, and metabolic adaptation. By modulating the activity of downstream targets, these cascades can influence the expression or activity of enzymes involved in triglyceride synthesis, lipoprotein assembly, or HDL remodeling, thereby indirectly affecting the level of triglycerides carried within very large HDL particles.
Systemic Lipid Dysregulation and Cardiovascular Risk
Section titled “Systemic Lipid Dysregulation and Cardiovascular Risk”The intricate interplay of metabolic, transcriptional, and signaling pathways ultimately determines systemic lipid concentrations, with direct implications for health outcomes. Studies have identified numerous genetic loci that influence lipid concentrations, including triglycerides and HDL, and these loci are often associated with an altered risk of coronary artery disease.[2]Dysregulation within these pathways can lead to adverse lipid profiles, such as elevated triglycerides and altered HDL composition, which are recognized risk factors for cardiovascular conditions.[10]Understanding these integrated mechanisms is critical for identifying potential therapeutic targets and developing strategies to mitigate disease risk by normalizing triglyceride levels in very large HDL and other lipoprotein classes.
Clinical Relevance
Section titled “Clinical Relevance”Prognostic Value and Cardiovascular Risk
Section titled “Prognostic Value and Cardiovascular Risk”Elevated triglyceride levels, even in a non-fasting state, have been associated with an increased risk of cardiovascular events, underscoring their prognostic significance in clinical practice. The integration of genetic profiles for lipid traits, including triglycerides, with traditional clinical risk factors such as age, BMI, and sex, has been shown to improve the classification of Coronary Heart Disease (CHD) risk. This enhanced risk stratification aids in identifying individuals at higher risk for adverse cardiovascular outcomes.[4]. [1]
Genetic risk scores, developed from identified loci associated with lipid levels, contribute explanatory value for predicting clinically relevant outcomes. While a combined genetic profile encompassing various lipid traits, and specifically a genetic risk profile for total cholesterol, demonstrated strong associations with outcomes like intima media thickness (IMT) and incident CHD, these studies confirm the broader utility of genetic insights into lipid metabolism for predicting disease progression. This supports the concept that genetic predisposition to dyslipidemia influences long-term cardiovascular health..[1]
Genetic Determinants and Personalized Risk Assessment
Section titled “Genetic Determinants and Personalized Risk Assessment”Genome-wide association studies have identified multiple common genetic variants that significantly contribute to the polygenic nature of dyslipidemia, including variations influencing triglyceride levels. Key genes such asGCKR, TRIB1, MLXIPL, NCAN, ANGPTL3, APOA5, and LPLhave been consistently associated with triglyceride concentrations. These genetic insights provide a foundation for understanding individual variations in lipid metabolism and offer pathways for more personalized risk assessment strategies.[3]. [2]
The construction of genetic risk scores based on these identified loci facilitates the identification of high-risk individuals and informs prevention strategies. Such scores can improve the prediction of conditions like hypercholesterolemia beyond traditional clinical factors, paving the way for targeted interventions. Furthermore, observed sex-specific effects for certain lipid-related variants, such as rs2083637 in LPL influencing HDL (a component of lipid metabolism often inversely related to triglycerides), highlight the need for tailored approaches in personalized medicine.. [1]
Interplay with Dyslipidemia and Metabolic Health
Section titled “Interplay with Dyslipidemia and Metabolic Health”Triglyceride levels are intrinsically linked to the broader spectrum of dyslipidemia, and genetic studies reveal overlapping associations that underpin this connection. For instance, an allele associated with increased LDL cholesterol concentrations nearNCAN (rs16996148 ) is also linked to increased triglyceride concentrations, reflecting a modest positive correlation between these two traits and suggesting shared genetic influences on lipid metabolism. This intricate relationship underscores the complex interplay between different lipid fractions in the pathogenesis of cardiovascular disease..[2]
The clinical utility of triglyceride assessment extends beyond fasting measurements, as genetic polymorphisms that influence fasting lipid levels also exert their effects in the more common “fed” state. This observation is particularly relevant given the association between nonfasting triglycerides and an increased risk of cardiovascular events, suggesting that triglyceride levels remain a pertinent biomarker for cardiovascular risk even outside of strict fasting conditions. This reinforces the importance of monitoring triglyceride levels as a component of overall metabolic health and cardiovascular disease prevention..[4]
References
Section titled “References”[1] 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.
[2] Willer CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet. 2008; 40:185–191.
[3] Kathiresan, S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008, PMID: 19060906.
[4] Wallace, C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, 2008. PMID: 18179892.
[5] Ober, C., et al. “Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q.”J Lipid Res, vol. 50, no. 6, 2009, pp. 1195-2003.
[6] Koishi R, et al. “Angptl3 regulates lipid metabolism in mice.” Nat Genet. 2002; 30:151–157.
[7] Romeo S, et al. “Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.” Nat Genet. 2007; 39:513–516.
[8] Murphy C, et al. “Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.” Biochem Biophys Res Commun. 2007; 355:359–364.
[9] Kiss-Toth E, et al. “Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.” J Biol Chem. 2004; 279:42703–42708.
[10] Samani NJ, et al. “Genomewide association analysis of coronary artery disease.”N Engl J Med. 2007; 357:443–453.