Phospholipids In Medium Ldl
Introduction
Section titled “Introduction”Background
Section titled “Background”Phospholipids are a major class of lipids that form the fundamental structural components of all cellular membranes and lipoproteins. Low-density lipoprotein (LDL) is a type of lipoprotein responsible for transporting cholesterol and other lipids, including phospholipids, from the liver to peripheral tissues.[1]The measurement of specific phospholipid species within medium LDL particles provides a detailed view of lipid metabolism and their intricate roles in the body. Lipoprotein particle concentrations, including those of low-density lipoproteins, are often measured using techniques such as nuclear magnetic resonance.[1]Variations in serum lipid levels, which include phospholipids, are highly heritable and are important determinants of cardiovascular disease and related morbidity.[2]
Biological Basis
Section titled “Biological Basis”Phospholipids within LDL particles contribute to the structural integrity and function of these lipoproteins, influencing their interaction with enzymes and receptors. The composition of phospholipids can be diverse, characterized by the presence of ester (diacyl) or ether (acyl-alkyl, dialkyl) bonds in the glycerol moiety and varying fatty acid side chains (e.g., Cx:y, where x is carbon count and y is double bonds). [3] Genetic factors play a significant role in determining phospholipid composition and their levels in lipoproteins. For instance, common genetic variants within the FADS1-FADS2 gene cluster, which encode desaturases, are associated with the fatty acid composition in phospholipids. [4] Genes such as LIPC (hepatic lipase) are involved in lipid metabolism, and genetic polymorphisms can affect its substrate specificity, potentially influencing phospholipid profiles, including phosphatidylethanolamines. [3]
Clinical Relevance
Section titled “Clinical Relevance”Abnormal levels of phospholipids in medium LDL, as part of broader dyslipidemia, are clinically relevant due to their strong association with cardiovascular diseases. Elevated LDL cholesterol levels are a well-established risk factor for coronary artery disease (CAD) and stroke.[2] Genetic variations influencing LDL levels have been identified across numerous loci, including APOB, PCSK9, LDLR, HMGCR, and others. [1]For example, specific single nucleotide polymorphisms (SNPs), such asrs16996148 near CILP2 and PBX4, have been associated with lower concentrations of both LDL cholesterol and triglycerides. [1] The association of specific phospholipid profiles with blood cholesterol levels suggests that these metabolic traits may serve as intermediate phenotypes, linking genetic variants to complex diseases. [3]
Social Importance
Section titled “Social Importance”Cardiovascular disease remains a leading cause of morbidity, mortality, and disability globally.[5] Understanding the role of specific phospholipids within medium LDL particles and their genetic determinants is crucial for advancing the prevention and treatment of these conditions. Research into polygenic dyslipidemia, which involves many genes and their common variants, helps to explain individual variability in lipid concentrations and contributes to identifying novel therapeutic targets. [1]By deciphering the complex interplay between genetics, phospholipid metabolism, and lipoprotein profiles, there is potential to develop more precise diagnostic tools and personalized interventions to manage cardiovascular risk in the population.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Common variants identified in these studies consistently demonstrate modest individual effects, collectively explaining only a small fraction (e.g., approximately 5%) of the interindividual variability in lipoprotein levels.[1] This limited explained variance indicates that a substantial portion of the genetic architecture influencing lipid traits remains to be discovered, suggesting the involvement of rare variants, structural variations, or complex interactions not fully captured by common SNP analyses. [2] Furthermore, the reliance on conditional analyses, where index SNPs are used as covariates, significantly reduces the number of independently significant associations, highlighting that many initial signals might be in linkage disequilibrium with primary loci rather than representing distinct genetic effects. [1]
Differences in study design and statistical approaches across cohorts introduce potential inconsistencies and challenges for meta-analysis. For instance, some studies explicitly accounted for relatedness using linear mixed-effects models, while others, primarily population-based, used linear regression for unrelated individuals. [1] Such methodological heterogeneity, including variable adjustments for factors like age-squared or the exclusion of outliers, can affect the comparability and interpretation of effect sizes and p-values across diverse datasets. [1] This variability might contribute to discrepancies observed in replication efforts, such as the mixed findings for HMGCR SNPs across different meta-analyses. [6]
Generalizability and Phenotype Heterogeneity
Section titled “Generalizability and Phenotype Heterogeneity”A significant limitation of many contributing studies is their predominant focus on populations of European ancestry. [2] While some efforts were made to replicate findings in multiethnic cohorts, the systematic exclusion of non-European individuals from primary analyses restricts the generalizability of these genetic associations to a broader global population. [2]Different linkage disequilibrium patterns and allele frequencies across diverse ancestries mean that discovered associations might not translate directly or have the same effect size in other ethnic groups, underscoring the need for more inclusive genomic research.[6]
Phenotypic measurements and participant characteristics also exhibit considerable heterogeneity across studies, which can confound genetic association analyses. For example, some cohorts lacked information on lipid-lowering therapy, necessitating the exclusion of individuals on such medications where possible, while others, like the ISIS study, predated widespread drug use. [1] Similarly, the availability of fasting lipid concentrations varied, a crucial factor for accurate lipid assessment, and differences in outlier handling or age adjustment further complicate cross-study comparisons. [1] These inconsistencies in phenotype ascertainment introduce noise and may obscure or misrepresent true genetic effects.
Unexplained Heritability and Complex Interactions
Section titled “Unexplained Heritability and Complex Interactions”Despite the identification of numerous common variants, a substantial proportion of the heritability of lipid traits remains unexplained, pointing to significant knowledge gaps in understanding polygenic dyslipidemia. [2]The observed genetic profiles, while valuable, only marginally improve the clinical prediction of cardiovascular disease compared to rare variants with larger effects, suggesting that the current understanding is far from complete.[2] Further characterization of the genetic landscape, including contributions from rare variants, epigenetic factors, and complex regulatory mechanisms, is essential to fully elucidate the heritable components of lipid levels. [2]
The interplay between genetic predisposition and environmental factors, alongside potential gene-gene interactions, represents a critical area that is largely unaddressed in the current framework. Discrepancies in replication and effect sizes across studies can be attributed to unaccounted environmental exposures or non-additive interactions among genetic variants. [6] For example, a locus including FADS1-FADS2 showed association with LDL after adjustment for BMI, indicating a potential gene-environment interaction or confounding. [7]Without comprehensive data on lifestyle, diet, and other environmental modifiers, the full impact of identified genetic variants and the mechanisms underlying polygenic dyslipidemia cannot be completely understood.
Variants
Section titled “Variants”The genetic landscape influencing lipid metabolism and cardiovascular disease risk is complex, involving numerous genes and single nucleotide polymorphisms (SNPs) that collectively impact the levels and composition of circulating lipoproteins, including phospholipids in medium low-density lipoprotein (LDL). These variants offer insights into the biological pathways governing cholesterol homeostasis and highlight potential targets for therapeutic intervention.
Among the well-studied genes influencing LDL are CELSR2 (cadherin, EGF LAG seven-pass G-type receptor 2) and PSRC1(proline/serine-rich coiled coil 1), located adjacent to each other on chromosome 1. Variants such asrs646776 and rs12740374 in this region are strongly associated with serum LDL levels. [8] This genetic influence assumes particular importance as the same allele at rs646776 has also been linked to an increased risk of coronary disease.PSRC1 is known to play a role as a microtubule-associated protein within the WNT/beta-catenin signaling pathway, a pathway functionally implicated in LDL processing in the liver, suggesting a mechanism by which these variants could affect the phospholipid composition and overall levels of medium LDL particles. [8]
Another critical set of genes involved in LDL regulation includes LDLR(low-density lipoprotein receptor) andPCSK9 (proprotein convertase subtilisin/kexin type 9). Variants in LDLR, such as rs73015024 and rs12151108 , can alter the efficiency with which LDL particles are cleared from the bloodstream, directly impacting circulating LDL levels and their associated phospholipid content. The PCSK9 gene, with variants like rs11591147 , rs11206517 , and rs472495 , modulates LDLR degradation; increased PCSK9activity leads to fewer functional receptors and higher medium LDL cholesterol. Common genetic variation influences biochemical parameters that are measured in everyday clinical care, including LDL levels, which are frequently measured biomarkers of cardiovascular risk.[8] Elevated cholesterol, largely due to high LDL, contributes to millions of deaths globally, emphasizing the significant clinical implications of these genetic variations. [8]
Further impacting lipid profiles are genes such as HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), APOB(apolipoprotein B), andTRIB1AL (Tribbles pseudokinase 1). HMGCR, represented by rs12916 , is the rate-limiting enzyme in cholesterol biosynthesis, and variations can affect the production of cholesterol and thus the phospholipid components of LDL. The APOB gene, with variants like rs563290 and rs562338 , encodes the primary structural protein of LDL particles, essential for their assembly and stability, and genetic variations here can influence the metabolism of medium LDL. Genetic influence on LDL levels and other biochemical parameters are important discoveries providing biological connections between genetic predispositions and cardiovascular outcomes.[8] Additionally, variants in TRIB1AL, such as rs28601761 and rs112875651 , are known to modulate the degradation of transcription factors involved in lipid synthesis, thereby influencing circulating LDL levels and their phospholipid content. [8]
Other genes, including NECTIN2 (Nectin Cell Adhesion Molecule 2), BCAM (Basal Cell Adhesion Molecule), ZPR1 (Zinc Finger Protein, RNA-binding 1), and CERT1 (Ceramide Transport Protein 1), also contribute to the polygenic architecture of lipid traits. For instance, variants like rs7254892 in NECTIN2 or rs118147862 in BCAMmay influence cellular processes that indirectly affect lipoprotein metabolism or vascular health, thereby subtly impacting medium LDL and its associated phospholipids. Studies continue to identify regions previously unknown to influence LDL, enhancing our understanding of cardiovascular risk.[8] While the specific mechanisms for variants such as rs964184 in ZPR1 and the rs12916 locus (also affecting CERT1) are still being characterized, the collective impact of these genetic variations underscores the complex inherited tendency to have altered lipid levels and may influence the phospholipid composition of circulating lipoproteins. [8]
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Key Variants
Section titled “Key Variants”Causes
Section titled “Causes”Genetic Foundations of Phospholipid and LDL Regulation
Section titled “Genetic Foundations of Phospholipid and LDL Regulation”The concentrations of phospholipids and low-density lipoprotein (LDL) are significantly influenced by a complex genetic architecture, encompassing both rare Mendelian forms of dyslipidemias and common polygenic variants. Numerous genes have been identified through genome-wide association studies (GWAS) as contributing to the variability of circulating lipid levels, including those involved in the synthesis, metabolism, and transport of lipoproteins and phospholipids.[2] Key loci impacting these levels include APOB, PCSK9, LDLR, LPL, LIPC, MLXIPL, TRIB1, GALNT2, CILP2-PBX4, ANGPTL3, APOA5-APOA4-APOC3-APOA1 cluster, APOE-APOC clusters, CETP, GCKR, HMGCR, ABCA1, SORT1, NCAN, MVK-MMAB, FADS1-FADS2, PSRC1/CELSR2, LCAT, and PLTP, each playing a distinct role in lipid homeostasis. [2] While rare, highly penetrant variants in genes like PCSK9 can cause autosomal dominant hypercholesterolemia with substantial effects on LDL levels, the majority of observed variability in the population is attributed to the cumulative modest effects of many common genetic variants, underscoring a polygenic basis for dyslipidemia. [9]
Specifically, genetic variants impact diverse aspects of lipid metabolism, from apolipoprotein structure and function (e.g., APOB, APOE) to enzyme activity and receptor degradation. For instance, single nucleotide polymorphisms (SNPs) inHMGCR are associated with LDL cholesterol levels and can affect the alternative splicing of its exon 13, thereby influencing cholesterol synthesis pathways. [6] Similarly, variants near CILP2 and PBX4 have been linked to lower concentrations of both LDL cholesterol and triglycerides, while polymorphisms in GALNT2suggest a role for enzymatic O-linked glycosylation in regulating HDL cholesterol and triglyceride metabolism, which indirectly impacts LDL.[1] The FADS1-FADS2 genes, encoding desaturases, show strong associations with various fatty acids present in serum phospholipids, further underscoring the direct genetic influence on phospholipid composition and its implications for overall lipid transport. [7]
Gene-Environment Interactions and Regulatory Mechanisms
Section titled “Gene-Environment Interactions and Regulatory Mechanisms”The genetic predisposition to altered phospholipid and LDL levels does not operate in isolation but is intricately modulated by gene-environment interactions and complex regulatory mechanisms that influence gene expression and protein function. Genetic variants can affect the transcript levels of key genes, thereby altering metabolic pathways. For example, specific alleles at the PLTP locus (rs7679 ) are associated with higher PLTP transcript levels, which in turn correlate with higher HDL cholesterol and lower triglycerides, demonstrating a gene-expression quantitative trait locus effect. [9] Likewise, LIPC promoter variants are associated with altered hepatic lipase activity and subsequent HDL cholesterol levels, indicating how genetic differences fine-tune lipid processing enzymes. [9]
Moreover, genetic polymorphisms can modify an individual’s susceptibility to diseases that affect lipid profiles, sometimes serving as intermediate phenotypes. A genetic polymorphism in LIPC, for instance, not only affects phosphatidylethanolamines but also shows weak associations with complex conditions such as type 2 diabetes, bipolar disorder, and rheumatoid arthritis.[3]This suggests that an individual’s genetic makeup can predispose them to certain metabolic traits that, when combined with environmental triggers or lifestyle choices, contribute to the manifestation of complex diseases, thereby influencing overall lipid and phospholipid homeostasis.[3]
Lifestyle, Comorbidities, and Age-Related Influences
Section titled “Lifestyle, Comorbidities, and Age-Related Influences”Beyond genetic factors, various lifestyle elements, co-existing medical conditions, and natural physiological changes associated with aging play a crucial role in determining phospholipid and LDL concentrations. Dietary patterns, as implied by studies conducted in populations like the Malmö Diet and Cancer Study, can significantly interact with genetic predispositions to influence lipid profiles.[1] While specific dietary components are not detailed, the context highlights the importance of such environmental factors in large-scale population studies that assess lipid levels.
Furthermore, comorbidities such as type 2 diabetes are frequently found in study samples investigating lipid levels, underscoring their impact on dyslipidemia. [2]The presence of diabetes, along with other health conditions like bipolar disorder and rheumatoid arthritis which show weak associations with certain lipid-related gene variants, can modify an individual’s lipid metabolism, often leading to unfavorable phospholipid and LDL levels.[3] Age is another significant, independent factor influencing lipid concentrations, with studies consistently accounting for age and its square (age^2) when analyzing lipid variance, suggesting that age-related physiological changes contribute to observed lipid profiles in the population. [1]
Molecular Foundations of Phospholipid Composition in Lipoproteins
Section titled “Molecular Foundations of Phospholipid Composition in Lipoproteins”Phospholipids are fundamental structural components of lipoproteins, forming a crucial monolayer at the surface of particles like medium-density lipoprotein (LDL) that encapsulates a core of hydrophobic lipids such as triglycerides and cholesterol esters. Their specific fatty acid composition influences the fluidity, stability, and function of these lipoprotein particles, which are essential for lipid transport throughout the body. The fatty acid desaturase genes,_FADS1_ and _FADS2_, play a direct role in determining the fatty acid composition within phospholipids. [4] Common genetic variants in the _FADS1_ _FADS2_ gene cluster are associated with the specific fatty acid makeup of phospholipids, indicating a genetic predisposition to variations in these crucial structural lipids. [4]
The broader metabolic environment, including triglyceride metabolism, also indirectly affects phospholipid content and composition in lipoproteins. For instance,_ANGPTL4_is a key biomolecule involved in regulating triglyceride levels, and variations in this gene have been observed to reduce triglycerides while increasing high-density lipoprotein (HDL).[10]Changes in triglyceride hydrolysis and remodeling processes impact the overall lipid exchange within lipoproteins, thereby influencing the relative proportions and types of phospholipids integrated into the LDL particle.
Genetic Modulators of Lipid and Lipoprotein Metabolism
Section titled “Genetic Modulators of Lipid and Lipoprotein Metabolism”Genetic mechanisms significantly regulate the pathways governing lipid and lipoprotein metabolism, directly impacting the characteristics of phospholipids in medium LDL. ATP-binding cassette transporters_ABCG5_ and _ABCG8_are critical for sterol efflux, and their genetic variants are associated with plasma lipoprotein levels.[11]These transporters influence the overall cholesterol balance within cells and lipoproteins, which can consequently affect the assembly and composition of lipoprotein particles, including their phospholipid surface.
Furthermore, transcription factors like _HNF4A_ (hepatocyte nuclear factor-4 alpha) regulate the expression of numerous genes involved in hepatic metabolism. Polymorphisms in _HNF4A_ are associated with metabolic conditions such as type 2 diabetes and altered beta-cell function. [12]Given the liver’s central role in lipoprotein synthesis and remodeling, variations in_HNF4A_ can indirectly influence the synthesis and trafficking of various lipid components, including the phospholipids that constitute lipoproteins like medium LDL. The complex interplay of multiple genetic loci contributes to polygenic dyslipidemia, where combinations of variants collectively affect lipid profiles. [1]
Systemic Regulation and Homeostatic Balance of Lipids
Section titled “Systemic Regulation and Homeostatic Balance of Lipids”Maintaining lipid homeostasis across tissues and organs is vital, with the liver serving as a central hub for lipoprotein synthesis, catabolism, and remodeling. The dynamic equilibrium of phospholipids in medium LDL is influenced by a network of enzymes, receptors, and transport proteins that coordinate lipid uptake, synthesis, and secretion. Disruptions in these regulatory networks, whether due to genetic variants or environmental factors, can lead to altered lipoprotein profiles and potentially impact the stability and function of circulating lipoproteins.
The interplay between hepatic lipid metabolism and systemic lipid transport pathways ensures that cells receive adequate lipids while preventing their accumulation in harmful amounts. For example, changes in triglyceride metabolism orchestrated by genes like_ANGPTL4_ [10] or the sterol efflux capabilities governed by _ABCG5_ and _ABCG8_ [11] can have systemic consequences, altering the lipid landscape of the plasma. These systemic effects, in turn, can modify the phospholipid composition and content of medium LDL, reflecting broader disruptions in lipid homeostasis.
Pathophysiological Relevance of Altered Phospholipid Profiles
Section titled “Pathophysiological Relevance of Altered Phospholipid Profiles”Variations in the phospholipid content and composition of medium LDL have significant pathophysiological implications, particularly in the context of metabolic diseases. An altered phospholipid profile can impact the structural integrity and biological interactions of LDL particles, affecting their recognition by cellular receptors and their susceptibility to oxidative modification. Such changes can contribute to the development and progression of conditions like dyslipidemia, which is characterized by abnormal lipid levels. [1]
Dyslipidemia, in itself, is a major risk factor for cardiovascular disease and other metabolic disorders. While the specific impact of phospholipids in medium LDL is intricate, deviations from optimal composition can impair the proper functioning of lipoproteins in lipid delivery and reverse cholesterol transport pathways. This can lead to homeostatic disruptions and contribute to the overall burden of metabolic dysfunction, as exemplified by the association of key metabolic regulators like_HNF4A_ with type 2 diabetes. [12]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Lipid Biosynthesis and Remodeling Pathways
Section titled “Lipid Biosynthesis and Remodeling Pathways”The intricate balance of phospholipids and other lipids, including their interaction with low-density lipoprotein (LDL), is governed by complex metabolic pathways. Phospholipid synthesis is crucial, with long-chain poly-unsaturated fatty acids, derived from essential fatty acids like linoleic acid, being fundamental components. Enzymes encoded by theFADS gene cluster, specifically FADS1 and FADS2, play a critical role in desaturation reactions, influencing the fatty acid composition within phospholipids such as phosphatidylcholine. [3] Genetic variants in this cluster are associated with the fatty acid composition in phospholipids, demonstrating a direct link between genetic predisposition and lipid molecular profiles. [4] Furthermore, the overall cholesterol pathway intersects with phospholipid metabolism, as phosphatidylethanolamines, for instance, are strongly affected by certain genetic polymorphisms and may play a role in cholesterol dynamics. [3]
Cholesterol biosynthesis itself involves key enzymes like mevalonate kinase (MVK), which catalyzes an early step in the mevalonate pathway, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), both of which are central to cholesterol production. [5] This biosynthetic activity is tightly regulated, and common genetic variants in HMGCR can influence alternative splicing, affecting the enzyme’s function and ultimately LDL cholesterol levels. [6] Concurrently, cholesterol degradation involves proteins like MMAB, highlighting the continuous flux and interdependency within lipid metabolic networks. [5]
Lipoprotein Dynamics and Catabolism
Section titled “Lipoprotein Dynamics and Catabolism”The regulation of circulating LDL levels relies on pathways governing its assembly, circulation, and catabolism. Apolipoprotein B (APOB) is a fundamental component of apoB-containing lipoproteins, including LDL, essential for their structural integrity and interactions. [2]The primary mechanism for LDL clearance from the bloodstream is its uptake by the low-density lipoprotein receptor (LDLR), a crucial protein on cell surfaces. [2] However, LDLR function is tightly controlled, notably by proprotein convertase subtilisin/kexin type 9 (PCSK9), which accelerates the degradation of LDLR in post-endoplasmic reticulum compartments, thereby reducing receptor availability and increasing circulating LDL cholesterol levels. [13]
Beyond receptor-mediated uptake, other factors significantly influence LDL catabolism and overall lipoprotein profiles. Apolipoprotein CIII (APOC3), secreted by the liver and intestines, is a component of both high-density lipoprotein (HDL) and apoB-containing lipoproteins. It impairs the catabolism and hepatic uptake of apoB-containing lipoproteins, contributing to dyslipidemia.[14]Lipases such as lipoprotein lipase (LPL) and hepatic lipase (LIPC) are essential for hydrolyzing triglycerides in lipoproteins, influencing their composition and size.[2] Their activities are further modulated by inhibitors like angiopoietin-like protein 4 (ANGPTL4), a potent factor that induces hyperlipidemia by inhibiting LPL, and ANGPTL3, another major regulator of lipid metabolism. [15] Lipid transfer proteins, such as phospholipid transfer protein (PLTP) and cholesterol ester transfer protein (CETP), mediate the exchange of phospholipids and cholesterol esters among lipoproteins, dynamically altering their lipid load and metabolic fate. [16]
Genetic and Molecular Regulatory Mechanisms
Section titled “Genetic and Molecular Regulatory Mechanisms”The regulation of phospholipid and LDL metabolism involves a sophisticated interplay of genetic, transcriptional, and post-translational controls. At the transcriptional level, factors like carbohydrate response element-binding protein (MLXIPL) serve as key activators of triglyceride synthesis genes, binding to specific motifs in their promoters.[5] This highlights how gene expression can be dynamically regulated to influence lipid production. Similarly, sterol regulatory element-binding protein 2 (SREBP2) regulates genes involved in cholesterol metabolism, including MVK and MMAB, thereby coordinating the cellular response to cholesterol demand. [5]
Post-translational modifications and protein interactions represent another critical layer of regulation. The proteolytic action of PCSK9 on the LDLR exemplifies a crucial post-translational mechanism, where PCSK9 binds to LDLR and targets it for lysosomal degradation, significantly reducing LDLR abundance on the cell surface and impacting LDL clearance. [13] Moreover, subtle genetic variations, such as those in the promoter region of LIPC, can alter hepatic lipase activity, demonstrating how sequence differences can have functional consequences on enzyme efficacy and lipid profiles. [1]Even alternative splicing, as observed with common single nucleotide polymorphisms (SNPs) inHMGCR, can impact protein function by altering transcript processing, leading to changes in enzyme activity and subsequent LDL cholesterol levels. [6]
Systems-Level Integration and Disease Linkages
Section titled “Systems-Level Integration and Disease Linkages”The metabolism of phospholipids and LDL is not an isolated process but is deeply integrated into broader physiological networks, with pathway crosstalk and feedback loops contributing to overall metabolic homeostasis. Metabolic traits, including specific phospholipid profiles, often serve as intermediate phenotypes that bridge genetic variation to the risk of complex diseases. [3] For instance, genetic polymorphisms in the FADSgene cluster not only affect the composition of polyunsaturated fatty acids in phospholipids but are also associated with cardiovascular disease, underscoring the systemic impact of these lipid modifications.[17]
Dyslipidemia itself is recognized as a polygenic trait, meaning it is influenced by common variants across numerous loci, which collectively contribute to the observed variation in lipid concentrations. [1]Genome-wide association studies have identified a multitude of genes whose variants contribute to lipid levels and coronary heart disease risk, includingABCA1, APOB, CELSR2, CETP, DOCK7, GALNT2, GCKR, HMGCR, LDLR, LIPC, LIPG, LPL, MLXIPL, NCAN, PCSK9, and TRIB1, among others. [2]These genes regulate diverse aspects of lipoprotein formation, activity, and turnover, from apolipoprotein synthesis to cholesterol transport, lipase activity, and receptor function.[5]The dysregulation of these interconnected pathways and molecular mechanisms ultimately underlies the development and progression of various metabolic diseases, including hyperlipidemia, type 2 diabetes, and cardiovascular disease.[3]
Clinical Relevance
Section titled “Clinical Relevance”References
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[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. 11, June 2006, pp. 1745-1756.
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[15] Yoshida K, Shimizugawa T, Ono M, Furukawa H. “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.
[16] Jiang X, et al. “Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.”J. Lipid Res., vol. 44, 2003, pp. 1332–1341.
[17] Malerba G, et al. “SNPs of the FADS Gene Cluster are Associated with Polyunsaturated Fatty Acids in a Cohort of Patients with Cardiovascular Disease.”Lipids, vol. 43, 2008, pp. 289–299.