Intermediate Density Lipoprotein
Intermediate density lipoprotein (IDL) is a type of lipoprotein particle that plays a crucial role in lipid transport within the bloodstream.[1] It represents an intermediate stage in the metabolic pathway of very low-density lipoproteins (VLDL) to low-density lipoproteins (LDL). A comprehensive understanding of IDL’s characteristics and functions is vital for evaluating an individual’s lipid profile and its implications for overall health.
Biological Basis
Section titled “Biological Basis”IDL particles are generated through the breakdown of VLDL, primarily by the enzyme lipoprotein lipase. As VLDL loses triglycerides, its density increases, transforming it into IDL, which contains a mix of cholesterol esters and triglycerides. These IDL particles can either be further processed, largely by hepatic lipase, to become LDL particles, or they can be directly absorbed by the liver. Advanced techniques, such as high-throughput proton nuclear magnetic resonance (NMR) spectroscopy, allow for precise measurements of the composition and size of IDL and other lipoprotein subclasses, offering a more detailed insight into lipid metabolism than traditional blood lipid tests.[2]
Clinical Relevance
Section titled “Clinical Relevance”Variations in the levels and characteristics of lipoprotein subclasses, including IDL, have been linked to the development and progression of metabolic and cardiovascular diseases.[2], [3] Detailed metabolic profiling using high-resolution NMR measurements has been instrumental in identifying genetic regions associated with lipid and small molecule metabolism, as well as in assessing the pleiotropic effects of previously established genetic loci.[4]For instance, specific genetic pathways, such as the “regulation of pyruvate dehydrogenase (PDH) complex,” have shown associations with IDL and LDL lipoproteins, highlighting novel connections between these pathways and lipid metabolism.[4] Furthermore, the concentration of apoB-containing lipoproteins, which include IDL, is recognized as a significant factor in the pathogenesis of cardiovascular disease.[5]
Social Importance
Section titled “Social Importance”Cardiovascular diseases are a major global health concern.[6]Enhanced knowledge of IDL and other lipoprotein subclasses, supported by genetic research and advanced measurement methods, contributes to a better understanding of the underlying causes of cardio-metabolic disorders.[2] This scientific insight can facilitate the identification of new therapeutic targets and the development of more personalized strategies for the prevention and management of lipid-related conditions, thereby improving public health outcomes.
Methodological and Measurement Constraints
Section titled “Methodological and Measurement Constraints”Research into intermediate density lipoprotein (IDL) is subject to specific methodological limitations, particularly concerning the breadth of metabolic traits analyzed. While Nuclear Magnetic Resonance (NMR) spectroscopy platforms offer robust, high-throughput, and cost-effective analysis, enabling the inclusion of large participant cohorts, they typically measure a more limited number of metabolic traits compared to complementary methods like mass spectrometry.[5]Although mass spectrometry is more sensitive and can simultaneously quantify thousands of metabolites, it often involves smaller sample sizes and generally cannot provide the detailed analysis of lipoprotein subclasses, including IDL, that NMR platforms deliver.[5]This trade-off means that while comprehensive characterization of lipoprotein subclasses is achieved, the full spectrum of circulating metabolites that might interact with IDL metabolism may not be captured in a single study design.
Generalizability and Ancestry Bias
Section titled “Generalizability and Ancestry Bias”A significant limitation in understanding IDL and its genetic regulation stems from the demographic composition of study cohorts, which often predominantly feature individuals of European descent. This imbalance results in limited statistical power to detect associations within other ancestry groups, such as African ancestries, thereby hindering a global understanding of metabolic genetics.[5] While some ancestry-stratified comparisons suggest that discovered associations may be broadly transferable, the exclusion of non-European participants in large biobanks, like the UK Biobank, further restricts the generalizability of findings to a broader, more diverse population.[1]Consequently, the findings regarding IDL’s genetic underpinnings may not fully represent the diverse genetic and environmental landscapes influencing lipoprotein metabolism across different human populations, necessitating larger, more inclusive studies.
Incomplete Genetic Architecture and Mechanistic Understanding
Section titled “Incomplete Genetic Architecture and Mechanistic Understanding”Despite extensive genome-wide association studies (GWAS), the complete genetic architecture influencing intermediate density lipoprotein and other lipoprotein subclasses remains to be fully elucidated. Specifically, while numerous common genetic variants have been identified, there are still additional loci, particularly those involving low-frequency and rare variants, whose contributions to IDL variability are not yet fully understood.[2] The challenge is compounded by the complex regulatory mechanisms at play, where multiple association signals within established loci may suggest intricate interactions between coding and regulatory variants, or even the involvement of several nearby genes affecting trait variation.[2] Furthermore, in gene-dense genomic regions, the precise functional roles of individual genes are often poorly understood, which can impede accurate causal inference and a complete mechanistic understanding of how genetic variants impact IDL metabolism.[1]
Variants
Section titled “Variants”The genetic landscape influencing intermediate density lipoprotein (IDL) levels involves a diverse array of genes and their associated variants, each contributing to the complex pathways of lipid metabolism._LIPC_(Lipase C, Hepatic Type) is a key enzyme that plays a crucial role in the metabolism of various lipoproteins, including high-density lipoprotein (HDL), IDL, and low-density lipoprotein (LDL). It functions by hydrolyzing triglycerides and phospholipids within these particles, facilitating the conversion of IDL to LDL and remodeling HDL particles.[4] Variants such as rs1077835 , rs2070895 , rs1077834 , and rs588136 , which are associated with _LIPC_ and its antisense RNA _LIPC-AS1_, can influence the enzyme’s activity or expression, thereby affecting the clearance of triglyceride-rich lipoproteins and impacting circulating IDL levels. Reduced_LIPC_activity, often due to genetic variations, can lead to impaired IDL catabolism, resulting in elevated IDL and potentially increased cardiovascular risk._ALDH1A2_ (Aldehyde Dehydrogenase 1 Family Member A2) and its associated variants rs261290 , rs7177289 , and rs261291 , are involved in retinoic acid metabolism, a pathway that can indirectly modulate lipid metabolism and inflammatory responses, with high-throughput nuclear magnetic resonance (NMR) measurements offering a comprehensive view of such complex particle compositions.[2] The _LDLR_(Low-Density Lipoprotein Receptor) gene encodes the primary receptor responsible for clearing cholesterol-rich lipoproteins, including both LDL and IDL particles, from the bloodstream by facilitating their uptake into cells, particularly liver cells. Variants likers6511720 , rs2738445 , and rs2228671 can alter _LDLR_ function, leading to reduced receptor activity and consequently higher circulating levels of IDL and LDL.[4] _PCSK9_ (Proprotein Convertase Subtilisin/Kexin Type 9) is a secreted enzyme that regulates _LDLR_ levels by binding to the receptor and promoting its degradation in lysosomes. Genetic variations in _PCSK9_, such as rs11591147 , rs472495 , and rs11206517 , affect _LDLR_ expression, with gain-of-function variants leading to lower _LDLR_ levels and higher IDL/LDL, while loss-of-function variants have the opposite effect. The _SMARCA4_ - _LDLR_ locus, including variants rs73015024 , rs147985405 , and rs12151108 , suggests a potential regulatory interplay between chromatin remodeling protein _SMARCA4_ and _LDLR_expression, which could indirectly influence lipoprotein uptake and IDL metabolism, highlighting the complex genetic architecture of lipid traits.[2] While _ZPR1_ (Zinc Finger Protein, Receptors Associated Protein 1) and its associated variants rs964184 and rs3741298 are generally involved in cell proliferation and survival, the variant rs964184 has been notably linked to the _APOA5_gene, a critical regulator of plasma triglyceride levels and a component of the_APOA1/C3/A4/A5_ gene cluster.[5] _APOA5_plays a vital role in the catabolism of triglyceride-rich lipoproteins, including very low-density lipoprotein (VLDL) and IDL, by activating lipoprotein lipase. Thus, variants at this locus can significantly impact the processing and clearance of IDL. Other genes, such as_NECTIN2_ (Nectin Cell Adhesion Molecule 2) with variants rs7254892 , rs3745151 , and rs79701229 , _CBLC_ (Cbl Proto-Oncogene Like C) with variants rs112450640 and rs80168591 , and the _CEACAM16-AS1_ - _BCL3_ locus with variant rs621171160 , represent more complex or less directly characterized associations with IDL metabolism. These genes are involved in diverse cellular processes, from cell adhesion to immune regulation and signal transduction, and their influence on IDL levels may stem from broader metabolic or inflammatory pathways, exemplifying the intricate and pleiotropic nature of metabolic trait-associated loci.[5]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs261290 rs7177289 rs261291 | ALDH1A2 | level of phosphatidylethanolamine level of phosphatidylcholine high density lipoprotein cholesterol measurement triglyceride measurement, high density lipoprotein cholesterol measurement VLDL particle size |
| rs1077835 rs2070895 rs1077834 | ALDH1A2, LIPC | triglyceride measurement high density lipoprotein cholesterol measurement level of phosphatidylcholine level of phosphatidylethanolamine total cholesterol measurement |
| rs588136 | ALDH1A2, LIPC-AS1, LIPC | high density lipoprotein cholesterol measurement triglyceride measurement level of phosphatidylcholine level of phosphatidylethanolamine LDL particle size |
| rs112450640 rs80168591 | CBLC | Alzheimer disease, family history of Alzheimer’s disease body weight low density lipoprotein cholesterol measurement, lipid measurement low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, phospholipid amount |
| rs964184 rs3741298 | ZPR1 | very long-chain saturated fatty acid measurement coronary artery calcification vitamin K measurement total cholesterol measurement triglyceride measurement |
| rs11591147 rs472495 rs11206517 | PCSK9 | low density lipoprotein cholesterol measurement coronary artery disease osteoarthritis, knee response to statin, LDL cholesterol change measurement low density lipoprotein cholesterol measurement, alcohol consumption quality |
| rs6511720 rs2738445 rs2228671 | LDLR | coronary artery calcification atherosclerosis lipid measurement Abdominal Aortic Aneurysm low density lipoprotein cholesterol measurement |
| rs73015024 rs147985405 rs12151108 | SMARCA4 - LDLR | total cholesterol measurement low density lipoprotein cholesterol measurement phospholipids in medium LDL measurement phospholipids in VLDL measurement blood VLDL cholesterol amount |
| rs7254892 rs3745151 rs79701229 | NECTIN2 | total cholesterol measurement low density lipoprotein cholesterol measurement glycerophospholipid measurement apolipoprotein A 1 measurement apolipoprotein B measurement |
| rs62117160 | CEACAM16-AS1 - BCL3 | Alzheimer disease, family history of Alzheimer’s disease apolipoprotein A 1 measurement apolipoprotein B measurement C-reactive protein measurement cholesteryl ester 18:2 measurement |
Nature and Classification of Intermediate Density Lipoprotein (IDL)
Section titled “Nature and Classification of Intermediate Density Lipoprotein (IDL)”Intermediate density lipoprotein (IDL) represents a distinct class within the broader spectrum of lipoproteins, which are crucial macromolecular complexes responsible for the transport of lipids throughout the circulatory system.[1] Functionally, IDL serves as a transitional particle in the continuous metabolic cascade, bridging very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL).[1]This classification is primarily based on differences in density, size, and the specific lipid and apolipoprotein composition of the particles.[2]The precise characterization of IDL as a lipoprotein subclass is vital for understanding its role in metabolic processes, given that variations in lipoprotein subclasses are significantly associated with various metabolic and cardiovascular diseases.[2]Lipoproteins are broadly categorized into classes such as VLDL, IDL, LDL, and high-density lipoprotein (HDL), forming a nosological system that reflects their distinct roles in lipid metabolism.[1]IDL itself is not a monolithic entity but can be further characterized by its internal components, representing a more dimensional approach to its definition beyond simple categorical presence. This detailed classification allows for a more nuanced understanding of lipid transport and dyslipidemia, contributing to a comprehensive view of particle size and composition compared to conventional blood lipid profiles.[2]
Compositional Terminology and Clinical Significance
Section titled “Compositional Terminology and Clinical Significance”The terminology surrounding intermediate density lipoprotein extends to its specific compositional elements, providing a granular definition of its metabolic profile. Key terms used in research and clinical contexts include “Triglycerides in IDL” (IDL-TG), “Free cholesterol in IDL” (IDL-FC), “Concentration of IDL particles” (IDL-P), and “Cholesterol esters to total lipids ratio in IDL” (IDL-CE %).[4] These specific components are recognized as distinct metabolic biomarkers, offering detailed insights into the dynamics of lipid transport and potential disruptions in metabolic pathways.[7]The clinical and scientific significance of these IDL-specific traits lies in their robust associations with cardiovascular and metabolic diseases.[2]Identifying and quantifying these individual components within IDL helps researchers to uncover the etiological roles of genetic variants and to explore novel therapeutic targets for conditions such as coronary artery disease and type 2 diabetes.[2] Therefore, a comprehensive understanding of IDL’s detailed composition and the associated terminology is essential for both diagnostic evaluation and the advancement of precision medicine.
Measurement Approaches and Analytical Criteria
Section titled “Measurement Approaches and Analytical Criteria”The precise quantification of intermediate density lipoprotein and its constituent lipids relies heavily on advanced analytical methodologies, with high-throughput nuclear magnetic resonance (NMR) spectroscopy profiling being a primary approach.[7]This NMR-based platform enables a comprehensive and detailed assessment of lipoprotein particle size and composition, offering a more exhaustive view than traditional blood lipid profile measurements.[2] For research applications, such as genome-wide association studies, metabolic biomarkers including IDL components are typically measured in absolute concentration, often expressed in units like mmol/L.[7] Operational definitions for IDL measurement often involve the collection of non-fasting EDTA plasma samples, which are then processed for NMR analysis.[7] Following quantification, the measured levels of metabolite biomarkers are frequently transformed to a standard normal distribution, commonly through rank-based inverse normalization, to facilitate robust statistical comparisons and analyses.[7]These rigorous measurement approaches and analytical criteria are fundamental for accurately characterizing IDL and its associations with health and disease states.
Intermediate Density Lipoproteins: Nature and Role in Lipid Metabolism
Section titled “Intermediate Density Lipoproteins: Nature and Role in Lipid Metabolism”Intermediate density lipoprotein (IDL) represents a distinct subclass of lipoproteins that plays a crucial role in the intricate process of lipid transport within the body.[1]These particles are metabolic intermediates, forming during the catabolism of very-low-density lipoproteins (VLDL) and serving as precursors to low-density lipoproteins (LDL). IDL particles are characterized by their specific composition, which includes apolipoprotein B (APOB) as a primary structural protein, along with significant amounts of triglycerides and cholesterol esters.[8]The precise measurement of IDL particle size and composition is achieved through advanced techniques such as high-resolution proton nuclear magnetic resonance (NMR) spectroscopy, which offers a more comprehensive view of lipid metabolism compared to conventional lipid profiles.[2]These detailed measurements are vital for capturing the nuanced underlying biological processes associated with lipoprotein dynamics.[4]
Genetic Architecture of IDL Levels
Section titled “Genetic Architecture of IDL Levels”The variability in circulating IDL levels is significantly influenced by genetic factors, encompassing common, low-frequency, and rare genetic variants.[2]Genome-wide association studies (GWAS), particularly when integrated with the high-resolution data provided by NMR-based metabolic profiling, have been instrumental in identifying numerous genetic loci associated with lipoprotein subclasses, including IDL.[2]Specific genomic regions have been linked to quantitative traits like triglycerides in IDL, with associations observed at chromosomal positions such as 4:100014805 and 5:156398169.[2]Furthermore, research indicates an enrichment of rare variant associations in genes located near established GWAS signals for traditional lipid traits, suggesting these genes often function as effector transcripts that modulate high-resolution lipoprotein measurements, thereby impacting IDL levels.[4]
Molecular and Cellular Regulation of IDL Metabolism
Section titled “Molecular and Cellular Regulation of IDL Metabolism”Recent investigations have uncovered a novel and significant link between the “regulation of pyruvate dehydrogenase (PDH) complex” pathway and the metabolism of IDL and LDL lipoproteins.[4]This pathway, previously not widely recognized for its direct involvement in lipoprotein phenotypes, appears to exert its influence through the cumulative effect of loss-of-function (LoF) variants within its constituent genes.[4] For instance, a notable observation involved a carrier of the PDHX Gln248Ter variant, who presented with exceptionally high LDL-C levels, highlighting the pathway’s critical role in systemic lipid regulation.[4]The PDH complex is a vital enzymatic system responsible for converting pyruvate into acetyl-CoA, a central hub molecule that connects glycolysis to the citric acid cycle and fatty acid synthesis, thereby profoundly impacting cellular energy production and overall lipid dynamics.
Clinical Significance and Disease Association
Section titled “Clinical Significance and Disease Association”The precise regulation of IDL levels and composition holds substantial clinical significance, as their dysregulation is closely implicated in the development and progression of various metabolic and cardiovascular diseases.[2]Abnormal IDL metabolism can disrupt systemic lipid homeostasis, contributing to atherosclerotic processes and increasing the risk of adverse cardiovascular events. A deeper understanding of the genetic and molecular mechanisms that govern IDL levels is therefore crucial for deciphering the complex etiology of these widespread cardio-metabolic conditions.[2] The ongoing detailed characterization of genetic contributions to IDL variability, including the identification of novel regulatory pathways like the PDH complex, offers promising avenues for the discovery of new therapeutic targets aimed at preventing and treating these diseases.[2]
Metabolic Regulation of Lipoprotein Dynamics
Section titled “Metabolic Regulation of Lipoprotein Dynamics”The metabolism of intermediate density lipoprotein (IDL) is intricately linked to core energy metabolism pathways, particularly those involving glucose and lipid catabolism. The “regulation of pyruvate dehydrogenase (PDH) complex” pathway has been newly associated with various traits, predominantly related to IDL and low-density lipoprotein (LDL).[4]This pathway is crucial for converting pyruvate into acetyl-CoA, a key substrate for the tricarboxylic acid cycle and fatty acid synthesis. Loss-of-function (LoF) variants in genes within this complex, such as a Gln248Ter variant inPDHX, can significantly impact metabolic flux, leading to elevated circulating LDL-C levels, thereby establishing a novel link between this fundamental metabolic process and lipoprotein metabolism.[4] Furthermore, enzymes like sterol O-acyltransferase 2 (SOAT2) play a direct role in cholesterol metabolism, while glycerol-3-phosphate acyltransferases are rate-limiting enzymes in triacylglycerol biosynthesis, directly influencing the lipid cargo and composition of lipoproteins.[5]
Genetic Modulators of Lipid Processing
Section titled “Genetic Modulators of Lipid Processing”Genetic variation profoundly influences the pathways governing IDL processing and clearance. Rare variant associations in genes located near established Genome-Wide Association Study (GWAS) signals for traditional lipid traits, such as HDL-C, LDL-C, total cholesterol (TC), and triglycerides (TG), are significantly enriched for associations with high-resolution lipoprotein measures.[4] Key genetic loci and genes implicated in lipid processing include the LPAlocus, which demonstrates a strong link to very-low-density lipoprotein (VLDL) metabolism and has a causal role in overall lipoprotein metabolism.[4] Additionally, genes such as LDLR(low-density lipoprotein receptor),APOB(apolipoprotein B), andPCSK9(proprotein convertase subtilisin/kexin type 9) are robustly established as candidate drug targets for cardiovascular disease, highlighting their central roles in lipoprotein uptake and regulation.[4] The LDL-RAP1(low-density lipoprotein receptor adapter protein 1) locus, known for its association with LDL-C and triglycerides, has also been linked to multiple lipoprotein subclass measures, indicating its broader impact on lipid homeostasis.[5]
Intracellular Signaling and Transcriptional Control
Section titled “Intracellular Signaling and Transcriptional Control”Intracellular signaling cascades and transcriptional regulation are critical for fine-tuning lipoprotein metabolism. The hypoxia-inducible factor 3 alpha (HIF3A) gene, a negative regulator of HIF1A (hypoxia-inducible factor 1, alpha subunit), influences the cellular uptake of cholesterol esters and VLDL by modulating hypoxic conditions.[2] Variants within the HIF3A promoter and intron 1 regions, particularly those associated with hyper-methylation, can affect its transcription and lead to altered phospholipid content in small VLDL particles, thus impacting IDL formation.[2] Another crucial regulatory mechanism involves AMP-activated protein kinase (AMPK), which suppresses the expression of ANGPTL8 (angiopoietin-like 8) in hepatic cells, thereby influencing lipid metabolism.[2] Furthermore, the F-box protein family, including FBXO36, is known to be involved in protein ubiquitination, a post-translational modification essential for protein degradation and the regulation of various metabolic enzymes and receptors.[4]
Systems-Level Lipid Homeostasis and Crosstalk
Section titled “Systems-Level Lipid Homeostasis and Crosstalk”Lipoprotein metabolism is characterized by extensive pathway crosstalk and network interactions that maintain systemic lipid homeostasis. TheANGPTL3 (angiopoietin-like 3) gene, for instance, plays a significant role in regulating adipose tissue energy homeostasis, while ANGPTL4directly regulates lipoprotein lipase, an enzyme critical for triglyceride hydrolysis and the maturation of VLDL to IDL and LDL.[2] The synthesis of fatty acids, particularly long-chain omega-3 and omega-6 polyunsaturated fatty acids, is modulated by polymorphisms in genes like FADS1 and FADS2.[8] A human-specific haplotype has been identified that increases the biosynthesis of these fatty acids, demonstrating a genetic adaptation influencing systemic lipid profiles.[8] These intricate interactions underscore how alterations in one pathway can propagate throughout the lipid network, influencing the overall composition and concentration of circulating lipoproteins, including IDL.
Dysregulation and Therapeutic Insights
Section titled “Dysregulation and Therapeutic Insights”Dysregulation in lipoprotein pathways contributes significantly to metabolic diseases and offers targets for therapeutic intervention. Loss-of-function variants in the pyruvate dehydrogenase complex pathway represent a novel link to IDL and LDL metabolism, with carriers of specific variants exhibiting markedly high LDL-C levels.[4]This highlights how disruptions in fundamental metabolic processes can directly impact lipoprotein profiles. Furthermore, genes likeTRIM5 (tripartite motif containing 5) have been identified as potential therapeutic targets for lowering pro-atherogenic lipid levels. Its metabolic profile aligns with genes that facilitate LDL cholesterol intake into hepatocytes via the LDL receptor, suggesting that modulating TRIM5could offer a strategy to reduce cardiovascular disease risk.[5]Understanding these dysregulated pathways and their molecular components provides a basis for developing targeted therapies to normalize IDL and other lipoprotein levels.
Risk Assessment and Prognostic Value
Section titled “Risk Assessment and Prognostic Value”Intermediate density lipoprotein (IDL), as a specific lipoprotein subclass, is significantly associated with metabolic and cardiovascular diseases.[2]High-throughput nuclear magnetic resonance (NMR)-based measurements provide a detailed view of lipoprotein particle size and composition, offering a more comprehensive assessment than conventional blood lipid profiles, and these expanded traits have been linked to various metabolic and cardiovascular conditions.[2]Metabolite profiling, which includes detailed lipoprotein subfractions like IDL, has been utilized in prospective studies to evaluate cardiovascular event risk, highlighting its potential in identifying individuals at elevated risk for adverse outcomes.[3]This detailed characterization contributes to more refined risk stratification, aiding in the prediction of disease progression and long-term implications, and supporting personalized medicine approaches.
The granular information derived from IDL components, such as triglycerides in IDL (IDL-TG), free cholesterol in IDL (IDL-FC), concentration of IDL particles (IDL-P), and cholesterol esters to total lipids ratio in IDL (IDL-CE %), can enhance prognostic models.[4]Understanding the specific lipid cargo and particle numbers within IDL allows for a more nuanced assessment of an individual’s metabolic health. This precision in risk assessment supports the development of targeted prevention strategies by identifying high-risk individuals who may benefit from early or more aggressive interventions to mitigate disease development.[3]
Clinical Applications and Monitoring Strategies
Section titled “Clinical Applications and Monitoring Strategies”The diagnostic utility of IDL lies in its capacity to offer insights into lipoprotein metabolism that extend beyond the scope of traditional lipid panels.[2] High-resolution NMR spectroscopy platforms, widely employed in large population cohorts such as the UK Biobank, quantify various IDL components from non-fasting plasma samples, thereby establishing a robust methodology for clinical assessment.[7] This detailed metabolic profiling is crucial for guiding treatment selection, particularly in the context of lipid-modifying therapies, by providing a more complete picture of an individual’s lipid profile.
Monitoring strategies can effectively leverage the tracking of IDL particle and cholesterol concentrations, especially when evaluating responses to therapeutic interventions. For instance, genetic studies have shown that pharmacological targeting of cholesteryl ester transfer protein (CETP) can lead to a genetically predicted reduction in IDL lipoprotein particle and cholesterol concentrations.[1] Such specific metabolic signatures are invaluable for assessing treatment efficacy, enabling clinicians to make informed adjustments to patient care plans and optimize therapeutic outcomes.
Genetic Associations and Comorbidities
Section titled “Genetic Associations and Comorbidities”Genetic studies, including genome-wide association studies (GWAS), are instrumental in elucidating the underlying genetic contributions to the variability observed in IDL subclass traits.[2] These studies frequently utilize high-throughput NMR metabolomics to pinpoint genomic loci associated with a wide array of metabolic traits, including IDL, thereby clarifying the genetic determinants of lipid metabolism.[1]A significant novel genetic association has been identified between the “regulation of pyruvate dehydrogenase (PDH) complex” pathway and both IDL and LDL lipoproteins, suggesting that cumulative effects of loss-of-function variants within genes of this pathway contribute to lipoprotein metabolism.[4] This genetic understanding of IDL metabolism illuminates its connections with overlapping phenotypes and potential comorbidities. For example, a specific carrier of the PDHXGln248Ter variant was observed to have exceptionally high low-density lipoprotein cholesterol (LDL-C) levels, highlighting the intricate relationship between IDL and broader lipoprotein metabolism.[4]Such insights are critical for refining risk stratification and advancing the development of more targeted prevention strategies for conditions like coronary artery disease and type 2 diabetes, which are often linked to dysregulated lipid profiles.[1]
References
Section titled “References”[1] Richardson, T. G., et al. “Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation.” PLoS Biol, 2022.
[2] Davis JP et al. “Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study.”PLoS Genet, vol. 13, no. 10, 2017, p. e1007024.
[3] Würtz, P, et al. “Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts.”Circulation, 2015.
[4] Riveros-Mckay F et al. “The influence of rare variants in circulating metabolic biomarkers.” PLoS Genet, vol. 16, no. 3, 2020, p. e1008631.
[5] Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature, vol. 627, no. 8003, 2024, pp. 433–442.
[6] World Health Organization. “Cardiovascular Diseases.”WHO, 2020, www.who.int/health-topics/cardiovascular-diseases/#tab=tab_1.
[7] Davyson, E. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.”Biol Psychiatry, 2023.
[8] Fuller, H., et al. “Metabolic drivers of dysglycemia in pregnancy: ethnic-specific GWAS of 146 metabolites and 1-sample Mendelian randomization analyses in a UK multi-ethnic birth cohort.”Front Endocrinol (Lausanne), 2023.