Triglycerides In Small Vldl
Introduction
Section titled “Introduction”Background
Section titled “Background”Triglycerides are the most common type of fat in the body, primarily serving as an energy storage molecule. They are composed of a glycerol backbone attached to three fatty acid chains. In the bloodstream, triglycerides are transported within lipoprotein particles, which are complex structures of lipids and proteins. Very low-density lipoproteins (VLDLs) are one such class of lipoproteins, synthesized by the liver to transport endogenous triglycerides to various tissues throughout the body. Small VLDL refers to a subfraction of VLDL particles that are characterized by their smaller size and denser composition. These smaller, denser lipoprotein particles are often associated with altered lipid metabolism and have distinct biological properties compared to larger VLDL particles.
Biological Basis
Section titled “Biological Basis”The production and metabolism of triglycerides in VLDL, including the small VLDL subfraction, are complex processes regulated by numerous genes and enzymatic pathways. The liver plays a central role in synthesizing triglycerides and packaging them into VLDL particles for secretion into circulation. Once in the bloodstream, VLDL particles undergo lipolysis by lipoprotein lipase, releasing fatty acids to peripheral tissues and transforming into VLDL remnants and eventually low-density lipoproteins (LDL). Genetic variations can significantly influence the levels of circulating triglycerides and the composition of lipoprotein particles. For instance, common genetic variants at several loci have been identified to contribute to polygenic dyslipidemia, a condition characterized by abnormal lipid levels.[1] The APOA5gene region, for example, has been shown to influence triglyceride levels in humans and mice.[2] Additionally, variations in genes like ANGPTL4can impact triglyceride levels, with some variants leading to reduced triglycerides and increased HDL.[3] Other genes, such as the FADS1 FADS2cluster, are associated with the fatty acid composition in phospholipids, which can indirectly affect triglyceride metabolism.[4] The precise regulation of these pathways determines the quantity and quality of VLDL particles, including the prevalence of small, dense subfractions.
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of triglycerides, particularly within small VLDL particles, are a significant clinical concern due to their strong association with increased risk for cardiovascular diseases, including coronary artery disease.[5]High triglycerides often accompany other unfavorable lipid profiles, such as low HDL cholesterol and the presence of small, dense LDL particles, collectively contributing to an atherogenic dyslipidemia. This lipid profile is a key component of metabolic syndrome, which also includes conditions like obesity, insulin resistance, and hypertension. Studies in children and adolescents, including those with obesity, have explored genetic factors like theMTNR1B gene variant rs10830963 that are associated with glucose levels and beta-cell function, highlighting the interconnectedness of lipid and glucose metabolism.[6]Understanding the genetic determinants of triglycerides in small VLDL can help identify individuals at higher risk for these conditions and guide personalized therapeutic interventions.
Social Importance
Section titled “Social Importance”The prevalence of elevated triglycerides and associated dyslipidemias represents a substantial public health burden globally. As dietary patterns and lifestyles shift towards increased consumption of processed foods and reduced physical activity, the incidence of obesity, type 2 diabetes, and cardiovascular diseases continues to rise. Triglycerides in small VLDL serve as an important biomarker and a modifiable risk factor in this broader context. Public health initiatives aimed at promoting healthy diets and regular exercise can impact triglyceride levels, but individual genetic predispositions also play a crucial role. Research into the genetics of lipid metabolism, including factors affecting small VLDL triglycerides, is vital for developing targeted prevention strategies, improved diagnostic tools, and more effective treatments to combat the societal impact of these chronic diseases.
Limitations
Section titled “Limitations”Study Design and Statistical Considerations
Section titled “Study Design and Statistical Considerations”The reliance on population-based cohorts in some studies aims to mitigate ascertainment bias, which can arise from including subjects selected for the presence or absence of a disease, yet this issue remains a general concern in genome-wide association studies.[7] Despite large sample sizes achieved through meta-analyses, some studies suggest that even larger samples and improved statistical power are necessary for the discovery of additional sequence variants. [1] Additionally, although promising signals are identified and replicated, some expected associations for triglycerides with specific genes, such as GALNT2, LIPC, and NCAN-CILP2-PBX4, have not been consistently replicated across all cohorts, pointing to potential replication gaps or study-specific influences. [8]
Ancestry, Phenotype Variability, and Sex-Specific Effects
Section titled “Ancestry, Phenotype Variability, and Sex-Specific Effects”A significant limitation in understanding the genetic architecture of triglycerides stems from the predominant focus on populations of European ancestry. Many studies explicitly excluded individuals of non-European ancestry or primarily included self-reported European participants. [9] While some efforts included multiethnic samples, the findings’ generalizability to diverse global populations remains limited without extensive replication in these groups. [9] Even within European ancestry, complex methods like ancestry-informative principal components were sometimes necessary to account for population substructure, highlighting the sensitivity to ancestral differences. [1]
Variations in phenotype measurement protocols across studies also introduce challenges. While fasting blood samples are generally required for triglyceride measurements, fasting times can vary, for example, from “at least 4 hours with a mean of 6 ± 4 hours” in one cohort.[9]The calculation of LDL cholesterol by Friedewald’s formula, and the exclusion of individuals with very high triglyceride levels, may also affect the consistency and comparability of lipid phenotypes.[9] Furthermore, some studies have noted significant differences in the effect sizes of certain genetic variants between males and females for lipid traits, indicating that a simple adjustment for sex might not fully capture the underlying sex-specific biological mechanisms and could potentially mask important genetic associations. [7]
Unexplained Variation and Environmental Influences
Section titled “Unexplained Variation and Environmental Influences”Despite the identification of numerous common genetic loci associated with triglyceride levels, these variants collectively explain only a small fraction of the total phenotypic variability within the population. For instance, the proportion of variance explained for triglycerides has been reported as low as 6% to 7.4%.[8]This substantial “missing heritability” suggests that much of the genetic and environmental architecture influencing triglyceride levels remains to be characterized. The current genetic profiles, while informative, offer only marginal improvement in the prediction of cardiovascular disease risk when added to traditional clinical risk factors.[7]
The limited explained variance points to significant knowledge gaps, potentially including the roles of rare variants with larger effects, complex structural variants, and epigenetic modifications, which are not fully captured by common SNP arrays. Moreover, environmental factors, gene-environment interactions, and lifestyle confounders (such as diet, physical activity, and socioeconomic status), while acknowledged and sometimes partially adjusted for, are not yet comprehensively integrated into genetic models. The intricate interplay between these unmeasured or poorly understood environmental factors and genetic predispositions likely contributes substantially to the unexplained variability in triglyceride levels, necessitating further research into their complex relationships to fully understand and predict triglyceride metabolism.
Variants
Section titled “Variants”Genetic variations play a crucial role in regulating lipid metabolism, significantly influencing the levels of triglycerides, particularly those carried within small very-low-density lipoprotein (VLDL) particles. A network of genes, includingLPL, ANGPTL4, GCKR, MLXIPL, TRIB1AL, APOB, BCL7B, TBL2, and others, harbor variants that collectively shape an individual’s lipid profile and risk for related metabolic conditions. These genes influence diverse pathways such as triglyceride hydrolysis, hepatic lipogenesis, and lipoprotein assembly and clearance.
Variants in LPL, or Lipoprotein Lipase, such asrs117199990 and rs144503444 , are significant determinants of triglyceride levels.LPL is an enzyme critically responsible for breaking down triglycerides in chylomicrons and VLDL particles into fatty acids for energy or storage. Reduced activity of LPLdue to certain genetic variants can lead to an accumulation of triglycerides in the bloodstream, contributing to higher levels of small VLDL particles and increasing cardiovascular risk. Conversely, the geneANGPTL4 (Angiopoietin-like 4) encodes a protein that acts as an inhibitor of LPL activity. The variant rs116843064 in ANGPTL4 may influence this inhibitory effect, potentially leading to altered LPLfunction and subsequent changes in circulating triglyceride levels, including those associated with small VLDL. This dynamic interplay betweenLPLand its regulators underscores the complexity of triglyceride homeostasis.[9]
Several genes are central to hepatic glucose and lipid metabolism, directly impacting VLDL triglyceride production. The geneGCKR(Glucokinase Regulator), with its variantrs1260326 , influences glucokinase activity in the liver, thereby affecting glucose phosphorylation and the rate of hepatic de novo lipogenesis, ultimately contributing to higher triglyceride levels and increased VLDL secretion. Similarly,MLXIPL(MAX-Like Protein X Interacting Protein-Like), also known as ChREBP, is a transcription factor that upregulates genes involved in fatty acid and triglyceride synthesis in response to carbohydrates. The variantrs34060476 in MLXIPLcan modify its transcriptional efficiency, altering hepatic lipid production and VLDL triglyceride content. Studies have identified associations of theMLXIPLregion with altered triglyceride and HDL cholesterol concentrations, where certain alleles are linked to lower triglycerides.[9] Another key regulator is TRIB1AL (Tribbles Pseudokinase 1), where variants like rs2954021 and rs28601761 can significantly impact triglyceride metabolism by influencing hepatic VLDL secretion and synthesis. Research indicates that specific alleles nearTRIB1 are strongly associated with lower triglycerides, lower LDL cholesterol, and higher HDL cholesterol, highlighting its prominent role in lipid modulation. [9]
The APOBgene (Apolipoprotein B) is fundamental for the structural integrity and metabolism of VLDL and LDL particles, crucial for their assembly and secretion from the liver. The variantrs2678379 in APOB can affect the efficiency of VLDL particle formation or clearance, directly influencing the amount of triglycerides transported within small VLDL. Adjacent or interacting with APOB is the LINC02850 - APOB region, where rs4665710 may exert regulatory effects on APOB expression or other lipid-related pathways, thus indirectly modulating VLDL levels. Furthermore, the region involving BCL7B (BCL7B Proto-Oncogene) and TBL2 (Transducin Beta Like 2) also contains relevant variants, such as rs13225450 . While BCL7B typically functions in chromatin remodeling, and TBL2is involved in broader cellular processes, genetic variations in this region have been associated with triglyceride and HDL cholesterol concentrations, suggesting an indirect or regulatory role in lipid metabolism.[9] Lastly, variations in less directly studied genes like RPL30P9 (rs115849089 ), a pseudogene, and ZPR1 (rs964184 ), involved in RNA processing, represent additional loci where variants may exert subtle yet collective influences on metabolic traits, potentially through regulatory interactions or by serving as markers for nearby functional variants affecting overall metabolic health.
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Definition and Physiological Context of Triglycerides in Small VLDL
Section titled “Definition and Physiological Context of Triglycerides in Small VLDL”Triglycerides in very low-density lipoprotein (VLDL) represent a key component of lipid metabolism, serving as a primary vehicle for transporting endogenous triglycerides synthesized by the liver to peripheral tissues. VLDL particles themselves are heterogeneous, existing in various sizes, with “small VLDL” referring to a particular subfraction that may have distinct metabolic implications.[9]The presence and concentration of triglycerides within these small VLDL particles are integral to understanding an individual’s lipid profile and overall cardiovascular risk, contributing to the broader category of dyslipidemia. This specific lipid measure reflects the efficiency of triglyceride synthesis, secretion, and subsequent catabolism within the body, distinguishing it from other lipoprotein components like low-, high-, and intermediate-density lipoproteins.[9]
Measurement Approaches and Associated Lipid Markers
Section titled “Measurement Approaches and Associated Lipid Markers”The concentration of VLDL particles, including small VLDL, is typically measured using advanced techniques such as nuclear magnetic resonance (NMR) spectroscopy. [9]This method allows for the quantification of specific lipoprotein particle concentrations, providing a more detailed assessment than traditional cholesterol measurements. In addition to VLDL particle concentrations, a comprehensive lipid panel often includes measures ofAPOA-I, APOB, APOC-III, and APOEapolipoproteins, along with HDL2 and HDL3 cholesterol subfractions, lipoprotein(a), and remnant lipoprotein cholesterol and triglycerides.[9] The interplay among these various lipid and apolipoprotein measures forms the basis for classifying different subtypes of dyslipidemia and identifying individuals at risk for related metabolic conditions.
Regulatory Factors and Clinical Significance
Section titled “Regulatory Factors and Clinical Significance”The metabolism of triglycerides in small VLDL is tightly regulated by various genetic and environmental factors, with specific apolipoproteins playing critical roles in their catabolism. For instance,APOC-IIIis a recognized inhibitor of triglyceride catabolism, meaning higher concentrations can lead to increased circulating triglycerides.[9] Research indicates that specific genetic variants, such as the GCKR P446L allele (rs1260326 ), are associated with increased concentrations of APOC-III, thereby influencing triglyceride levels.[9] Understanding the concentrations of triglycerides within small VLDL, alongside these regulatory proteins and genetic predispositions, is crucial for assessing an individual’s susceptibility to polygenic dyslipidemia and for developing targeted therapeutic strategies.
Causes
Section titled “Causes”Polygenic Architecture of Lipid Levels
Section titled “Polygenic Architecture of Lipid Levels”The levels of triglycerides within small very low-density lipoprotein (VLDL) particles are significantly influenced by a complex genetic architecture. Research indicates that common genetic variants located at numerous loci collectively contribute to a polygenic form of dyslipidemia.[9]This means that an individual’s predisposition to having altered triglycerides in small VLDL is not typically determined by a single genetic defect but rather by the cumulative impact of many common genetic variations, each having a subtle effect on lipid metabolism. These numerous variants work in concert, contributing to the broad range of triglyceride concentrations observed in the population.
Specific Genetic Variants and Their Mechanisms
Section titled “Specific Genetic Variants and Their Mechanisms”Specific genetic variants have been identified that directly modulate the metabolism of triglycerides. For instance, the rs1260326 allele in the GCKR gene, which results in the P446L protein variant, is strongly associated with elevated concentrations of APOC-III. [9] APOC-IIIis a protein primarily synthesized in the liver and functions as a critical inhibitor of triglyceride catabolism, meaning it impedes the breakdown and clearance of triglycerides from the bloodstream. Consequently, higher levels ofAPOC-IIIlead to reduced efficiency in triglyceride removal, thereby increasing their circulating concentrations, including those specifically found in small VLDL particles.[9]
Biological Background
Section titled “Biological Background”Transcriptional Control of Lipid Synthesis
Section titled “Transcriptional Control of Lipid Synthesis”The intricate balance of triglyceride levels, particularly within very-low-density lipoproteins (VLDL), is significantly influenced by genes that regulate lipid synthesis at the transcriptional level. One such gene,MLXIPL, encodes a protein that plays a crucial role by binding to and activating specific regulatory motifs found within the promoter regions of genes involved in triglyceride synthesis.[10]This direct interaction highlights a fundamental genetic mechanism where a protein dictates the rate at which cells produce the enzymes and structural components necessary for triglyceride formation, thereby impacting overall lipid metabolism. Furthermore, the expression of genes such asMVK and MMAB, both closely situated on the genome and sharing a common promoter, is under the control of SREBP2. [10] This co-regulation by SREBP2 underscores a coordinated genetic program governing aspects of lipid metabolism.
Regulation of Lipoprotein and Cholesterol Homeostasis
Section titled “Regulation of Lipoprotein and Cholesterol Homeostasis”Beyond synthesis, the broader regulation of lipid metabolism and cholesterol homeostasis is critical for maintaining healthy triglyceride levels. TheANGPTL3 gene, for instance, encodes a protein whose homolog in mice is a significant regulator of lipid metabolism. [10] This suggests a role for ANGPTL3in systemic lipid processing, which would inherently affect triglyceride concentrations and the composition of lipoproteins like VLDL. Related to this, rare genetic variations withinANGPTL4have been linked to changes in both high-density lipoprotein (HDL) and triglyceride concentrations in humans, indicating a shared regulatory pathway impacting multiple lipid classes.[10] Additionally, the genes MVK and MMAB contribute directly to cholesterol metabolism; MVK encodes mevalonate kinase, an enzyme essential for an early step in cholesterol biosynthesis, while MMAB encodes a protein that participates in a metabolic pathway responsible for cholesterol degradation. [10]Together, these genes illustrate the complex interplay of pathways that maintain lipid balance and influence the availability of precursors for triglyceride packaging into VLDL.
Modifiers of Lipoprotein Structure and Function
Section titled “Modifiers of Lipoprotein Structure and Function”The functional properties and clearance of lipoproteins, including VLDL, can also be influenced by post-translational modifications. The gene GALNT2 encodes a widely expressed glycosyltransferase, an enzyme responsible for attaching sugar molecules to proteins. [10] It is hypothesized that this enzyme could modify the structure of lipoproteins themselves or their associated receptors, thereby altering how these particles are recognized, metabolized, or cleared from circulation. [10]Such modifications could impact the stability, half-life, or cellular uptake of VLDL particles, directly affecting circulating triglyceride levels. While a direct connection to cholesterol metabolism forGALNT2was not established, its potential role in modulating lipoprotein function highlights an additional layer of complexity in the regulation of lipid profiles.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Transcriptional and Post-Translational Regulation of Lipid Homeostasis
Section titled “Transcriptional and Post-Translational Regulation of Lipid Homeostasis”The intricate regulation of triglyceride levels in small VLDL particles involves a network of transcriptional and post-translational controls. For instance, the protein encoded byMLXIPLdirectly influences lipid synthesis by binding to and activating specific motifs within the promoters of triglyceride synthesis genes, thereby regulating their expression and subsequent lipid production.[10] Similarly, SREBP2 acts as a key transcription factor, orchestrating the regulation of genes such as MVK, which is essential for cholesterol biosynthesis, and MMAB, involved in cholesterol degradation. [10] This transcriptional fine-tuning dictates the availability of precursors and enzymes crucial for lipid metabolism.
Beyond gene expression, protein modification plays a significant role, exemplified by GALNT2, a glycosyltransferase that can potentially modify lipoproteins or their receptors. [10] O-linked glycosylation, in which GALNT2is involved, serves as a broad regulatory mechanism for numerous proteins, including those central to HDL cholesterol and triglyceride metabolism.[9] Furthermore, post-translational inhibitors like ANGPTL3 act as a major regulator of lipid metabolism by inhibiting lipases, while its related protein ANGPTL4is a potent inhibitor of lipoprotein lipase (LPL), impacting triglyceride catabolism[10]. [11] The protein TRIB1 also contributes to this regulatory landscape by influencing the activity of mitogen-activated protein kinases (MAPK), suggesting a role in signaling pathways that converge on lipid metabolism. [10]
Metabolic Flux in Lipoprotein and Sterol Pathways
Section titled “Metabolic Flux in Lipoprotein and Sterol Pathways”The metabolism of triglycerides is deeply intertwined with broader lipid and sterol pathways, with several key enzymes and transporters governing metabolic flux. MVK encodes mevalonate kinase, an enzyme that catalyzes an early, rate-limiting step in the biosynthesis of cholesterol. [10] In contrast, MMAB encodes a protein that participates in a distinct metabolic pathway responsible for cholesterol degradation, collectively demonstrating coordinated control over cholesterol availability. [10] These pathways are not isolated but are tightly regulated, with both MVK and MMAB sharing a common promoter and being regulated by SREBP2. [10]
The dynamics of fatty acid composition are influenced by the FADS2-FADS3 gene cluster, which encodes proteins regulating the desaturation of fatty acids by introducing double bonds at specific carbons of the acyl chain. [7]This process impacts the types of fatty acids available for triglyceride synthesis and esterification. Additionally, the efflux of dietary cholesterol and noncholesterol sterols from the intestine and liver is managed byABCG5, which functions as a half-transporter that dimerizes with ABCG8 to form a functional complex. [7] The coordinated actions of these metabolic pathways are fundamental to maintaining overall lipid homeostasis and influencing the composition and concentration of triglycerides.
Interactions in Lipoprotein Assembly and Catabolism
Section titled “Interactions in Lipoprotein Assembly and Catabolism”The life cycle of lipoproteins, including the assembly, secretion, and catabolism of VLDL, is governed by a complex interplay of apolipoproteins, enzymes, and receptors. Genes encoding apolipoproteins such as APOE, APOB, APOA5, APOA4, APOC3, and APOA1are integral components, dictating the structure and function of lipoprotein particles and their interaction with metabolic enzymes[10]. [7] For instance, APOC3 transgenic mice exhibit hypertriglyceridemia, characterized by a diminished VLDL fractional catabolic rate linked to increased APOC3 and reduced APOE on the particles, highlighting the critical role of these apolipoproteins in VLDL clearance. [12]
Lipoprotein lipases, includingLPL, LIPC, and LIPG, are essential for the hydrolysis of triglycerides within circulating lipoproteins, facilitating the release of fatty acids for tissue uptake [10]. [7] The activity of LPL is tightly controlled by inhibitors such as ANGPTL3 and ANGPTL4, which directly impact the rate of VLDL triglyceride breakdown[10]. [11] Furthermore, endocytic receptors like SORT1 play a role in the turnover of LPLby binding to and mediating its degradation, adding another layer of regulation to triglyceride catabolism[10]. [13]This integrated network of components ensures the dynamic regulation of triglyceride concentrations in the bloodstream.
Genetic Modulators and Cardiometabolic Implications
Section titled “Genetic Modulators and Cardiometabolic Implications”Variations in genes involved in lipid metabolism have significant implications for plasma triglyceride levels and the risk of cardiovascular disease. Common genetic variants in loci nearMLXIPL, ANGPTL3, GCKR, LPL, APOA5-APOA4-APOC3-APOA1 cluster, and MVK-MMABhave been consistently associated with plasma triglyceride concentrations[7], [9], [10], [14]. [8] For example, a nonsynonymous coding SNP in the NCAN gene, rs2228603 (Pro92Ser), showed a strong association with increased triglyceride concentrations.[10]These genetic polymorphisms collectively influence the entire cycle of lipoprotein formation, activity, and turnover, from apolipoproteins and transcription factors to enzymes, transporters, and receptors.[10]
The impact of these genetic variations extends to both fasting and non-fasting lipid levels, indicating their relevance in the common “fed” state, which is particularly significant given the association between non-fasting triglycerides and increased cardiovascular event risk.[15] Pathway dysregulation, such as that seen with increased APOC3in transgenic mice leading to hypertriglyceridemia, demonstrates a clear link between specific molecular mechanisms and disease phenotypes.[12] Conversely, a null mutation in human APOC3 is associated with a favorable plasma lipid profile and apparent cardioprotection, suggesting that modulating these pathways represents potential therapeutic targets. [16]
Clinical Relevance
Section titled “Clinical Relevance”Prognostic Value and Risk Assessment
Section titled “Prognostic Value and Risk Assessment”Elevated triglyceride levels are recognized as significant predictors of cardiovascular outcomes and disease progression, playing a crucial role in patient risk stratification. Research indicates that non-fasting triglyceride levels are associated with an increased risk of cardiovascular events, suggesting their utility beyond traditional fasting measurements in assessing risk.[15]Genetic risk scores constructed from loci associated with triglyceride levels provide additional explanatory value and can improve the classification of coronary heart disease (CHD) risk when combined with conventional clinical risk factors such as age, BMI, and sex.[7]For instance, specific alleles associated with increased triglyceride concentrations, particularly near theTRIB1gene, have also been linked to an elevated risk of coronary artery disease.[10]This highlights the long-term implications of triglyceride levels in predicting adverse cardiovascular events.
Genetic Insights and Diagnostic Utility in Dyslipidemia
Section titled “Genetic Insights and Diagnostic Utility in Dyslipidemia”Genome-wide association studies (GWAS) have advanced the understanding of the genetic architecture underlying triglyceride regulation, identifying multiple loci that influence circulating levels. These include variants nearTBL2 and MLXIPL, TRIB1, GALNT2, CILP2-PBX4, and ANGPTL3, among others, which collectively contribute to polygenic dyslipidemia. [9] Some genetic variants show an association with multiple lipid traits; for example, alleles near CILP2-PBX4 and the NCANgene have been found to influence both LDL cholesterol and triglyceride concentrations.[9]The identification of these genetic determinants enhances diagnostic utility by providing insights into individual predispositions to dyslipidemia and can help characterize overlapping phenotypes with related conditions. While the estimated effect sizes for individual genetic associations may be modest, the collective contribution of these loci explains a notable proportion of the total variability in triglyceride levels.[8]
Clinical Management and Prevention Strategies
Section titled “Clinical Management and Prevention Strategies”Understanding the genetic and clinical factors influencing triglyceride levels offers avenues for personalized medicine and refined prevention strategies. The observation that genetic polymorphisms influencing fasting lipid levels also exert their effects in the non-fasting state is clinically important, especially given the established link between non-fasting triglycerides and increased cardiovascular event risk.[15]This suggests that monitoring strategies may need to account for both fasting and fed states to comprehensively assess patient risk. Although many studies exclude individuals on lipid-lowering therapy to isolate genetic effects, the identification of genetic loci associated with triglyceride levels could inform future treatment selection and personalized interventions.[9]Integrating genetic risk profiles with traditional clinical risk factors holds promise for more precise identification of high-risk individuals and the implementation of targeted prevention programs for conditions like coronary heart disease.[7]
References
Section titled “References”[1] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 12, Dec. 2009, pp. 1191-98.
[2] Pennacchio, Len A., et al. “An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.” Science, vol. 294, no. 5547, 2001, pp. 169–173.
[3] Romeo, S., et al. “Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.” Nat Genet, vol. 39, no. 4, 2007, pp. 513–516.
[4] 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, vol. 15, no. 10, 2006, pp. 1745–1756.
[5] Sarwar, Nita, et al. “Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.”Lancet, vol. 375, no. 9726, 2010, pp. 1634–1639.
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[8] Sabatti, C. et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 40, 2008, pp. 131–138.
[9] Kathiresan S, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008;40(2):189-97.
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[11] Yoshida, K. et al. “Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase.”J. Lipid Res., vol. 43, 2002, pp. 1770–1772.
[12] 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.”J. Clin. Invest., vol. 90, 1992, pp. 1889–1900.
[13] Nielsen, M.S. et al. “Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase.”J Biol Chem, vol. 274, 1999, pp. 8832–8836.
[14] Kooner, J. S., et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, vol. 40, no. 2, Feb. 2008, pp. 149-51.
[15] 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, 2008, pp. 1025–1039.
[16] Pollin, T.I. et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, 2008, pp. 1702–1705.