Cholesterol In Idl
Introduction
Section titled “Introduction”Background
Section titled “Background”Intermediate-density lipoprotein (IDL) is a type of lipoprotein particle found in the blood. Lipoproteins are complex particles that transport fats, such as cholesterol and triglycerides, through the bloodstream. Cholesterol in IDL refers to the amount of cholesterol carried specifically within these IDL particles. IDL represents a transient stage in the metabolism of very-low-density lipoproteins (VLDL) into low-density lipoproteins (LDL), playing a crucial role in the continuous cycle of lipid transport.
Biological Basis
Section titled “Biological Basis”IDL particles are formed from the catabolism of VLDL. After VLDL releases much of its triglyceride content to peripheral tissues via the action of lipoprotein lipase (LPL), it becomes an IDL particle, which is enriched in cholesterol esters. These IDL particles can then be taken up directly by the liver through receptors such as the LDL receptor (LDLR), often facilitated by apolipoprotein E (APOE), or further metabolized by hepatic lipase (HL) into LDL particles. Therefore, cholesterol in IDL represents a pool of cholesterol that is either destined for direct hepatic uptake or for conversion into the more prevalent LDL cholesterol.
Clinical Relevance
Section titled “Clinical Relevance”Levels of cholesterol in IDL are clinically relevant due to their association with cardiovascular health. Elevated IDL cholesterol is indicative of dyslipidemia and is considered an atherogenic lipoprotein, meaning it can contribute to the development of atherosclerosis, the hardening and narrowing of arteries. While not a standard measurement in routine lipid panels, high IDL cholesterol levels can contribute to overall cardiovascular risk and may be a target for therapeutic interventions aimed at managing lipid profiles and preventing heart disease.
Social Importance
Section titled “Social Importance”Understanding cholesterol in IDL contributes to the broader public health efforts in combating cardiovascular disease, which remains a leading cause of mortality worldwide. Insights into IDL metabolism help in developing targeted strategies for lifestyle modifications, dietary recommendations, and pharmaceutical interventions to manage lipid disorders. By recognizing the role of IDL in the lipoprotein cascade, individuals and healthcare providers can better assess personal risk for heart disease and implement more personalized approaches to maintaining cardiovascular health and overall well-being.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Genetic studies of cholesterol in IDL, particularly genome-wide association studies (GWAS), are subject to certain methodological and statistical constraints that can influence the interpretation of findings. While large sample sizes are crucial for detecting genetic variants with small effect sizes, the initial discovery of associations may sometimes overestimate the true effect size, a phenomenon known as winner’s curse, which typically attenuates upon replication in independent cohorts. Furthermore, the ability to identify rare genetic variants or those with very subtle effects remains challenging, potentially leading to an incomplete picture of the genetic architecture underlying cholesterol in IDL. The absence of consistent replication across diverse studies can also highlight issues related to statistical power, population-specific effects, or unaddressed confounding factors.
Population and Phenotype Heterogeneity
Section titled “Population and Phenotype Heterogeneity”A significant limitation in understanding the genetics of cholesterol in IDL stems from issues of ancestry and generalizability. Many large-scale genetic studies have historically focused on populations of European ancestry, which can limit the direct applicability of identified genetic associations to individuals from other ancestral backgrounds. Different populations may possess unique genetic architectures, allele frequencies, or linkage disequilibrium patterns, meaning that variants found in one group may not be relevant or have the same effect in another. Moreover, the precise measurement and definition of cholesterol in IDL can vary across studies, leading to phenotype heterogeneity. Differences in laboratory assays, fasting status, or the calculation methods for IDL cholesterol can introduce variability and impact the consistency and comparability of genetic findings across different research settings.
Complex Interactions and Unexplained Variance
Section titled “Complex Interactions and Unexplained Variance”The genetic contribution to cholesterol in IDL is undeniably complex, and current research faces limitations in fully accounting for all influencing factors. Environmental factors, such as diet, lifestyle, physical activity, and medication use, significantly interact with genetic predispositions, making it challenging to isolate the independent effect of any single genetic variant. Gene-environment interactions imply that the effect of a specific gene might only be apparent or significantly altered under particular environmental conditions, which are often difficult to comprehensively capture and model in genetic studies. Furthermore, a portion of the estimated heritability of cholesterol in IDL, known as “missing heritability,” remains unexplained by currently identified common genetic variants, suggesting that rare variants, structural variations, epigenetic factors, or more complex gene-gene interactions may play a substantial, yet uncharacterized, role.
Variants
Section titled “Variants”Genetic variations play a significant role in determining an individual’s cholesterol levels, including intermediate-density lipoprotein (IDL) cholesterol, which is a key precursor to low-density lipoprotein (LDL) cholesterol and an important marker of cardiovascular risk. Variants in genes central to lipoprotein metabolism, such asLDLR, PCSK9, and APOB, directly impact the clearance and production of IDL particles. For instance, the rs12151108 variant near the SMARCA4 - LDLRlocus can influence the expression or function of the low-density lipoprotein receptor (LDLR), a critical protein responsible for removing IDL and LDL from the bloodstream. Reduced LDLRactivity due to such variants can lead to higher circulating IDL cholesterol levels, increasing the risk of atherosclerosis..[1] Similarly, variations within the PCSK9 gene, including rs11591147 , rs11206517 , and rs472495 , are known to affect the activity of the PCSK9 protein, which degrades LDLR. Certain alleles can lead to increased PCSK9 activity, reducing LDLR availability and consequently elevating IDL and LDL cholesterol.. [1] The rs562338 variant, located near APOB - TDRD15, is relevant because APOB(Apolipoprotein B) is the primary structural protein of IDL and LDL particles; variations inAPOBcan affect lipoprotein assembly, secretion, or receptor binding, thereby influencing IDL cholesterol concentrations.
Other genes involved in cholesterol synthesis and transport also contribute to IDL cholesterol variability. The rs3843480 variant in the ANKRD31 - HMGCR region is particularly notable due to its proximity to HMGCR (HMG-CoA Reductase), the rate-limiting enzyme in cholesterol biosynthesis. Genetic variations that affect HMGCR activity can alter the overall production of cholesterol, which in turn influences the availability of cholesterol for VLDL and subsequent IDL formation, impacting circulating IDL levels.. [1] Additionally, the rs12740374 variant near CELSR2 (Cadherin EGF LAG Seven-Pass G-Type Receptor 2) has been consistently associated with lipid levels. While its direct mechanism on IDL is still being elucidated, CELSR2 is part of a gene cluster on chromosome 1p13 that influences LDL cholesterol and likely, by extension, IDL metabolism through pathways related to hepatic lipid processing.. [1] The rs261290 variant in ALDH1A2 (Aldehyde Dehydrogenase 1 Family Member A2) and rs102275 in TMEM258 (Transmembrane Protein 258) are also implicated in lipid metabolism, with ALDH1A2 being involved in retinoic acid synthesis, a molecule known to influence gene expression related to lipid homeostasis, and TMEM258 being identified in genome-wide association studies for various lipid traits.
Beyond these core lipid metabolism genes, other loci contribute to the complex regulation of IDL cholesterol. The rs7254892 variant in NECTIN2(Nectin Cell Adhesion Molecule 2) has been linked to variations in lipid profiles, suggesting a potential role in cell-cell adhesion or signaling pathways that indirectly affect lipoprotein metabolism or vascular health..[1] The rs62117160 variant, located in the CEACAM16-AS1 - BCL3 region, may influence IDL cholesterol through effects on inflammation or gene regulation, as BCL3 (B-cell CLL/lymphoma 3) is a transcriptional co-regulator involved in immune responses that can impact metabolic processes. Furthermore, the rs115478735 variant in the ABO gene, which determines blood group, is associated with differences in circulating lipid levels, including IDL. Individuals with certain ABOblood types exhibit varying levels of lipid-carrying proteins and enzymes, such as lipoprotein lipase, which can affect the conversion of VLDL to IDL and the subsequent clearance of IDL particles..[1]These diverse genetic influences highlight the intricate network of pathways that collectively determine an individual’s IDL cholesterol levels and cardiovascular risk.
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology of Cholesterol in IDL
Section titled “Classification, Definition, and Terminology of Cholesterol in IDL”Definition and Composition of Intermediate-Density Lipoprotein (IDL)
Section titled “Definition and Composition of Intermediate-Density Lipoprotein (IDL)”Cholesterol in IDL refers to the cholesterol content carried within Intermediate-Density Lipoprotein particles circulating in the bloodstream. IDL represents a transient class of lipoproteins in the metabolic pathway between very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). These particles are formed as VLDL loses triglycerides through the action of lipoprotein lipase, becoming progressively denser. IDL particles are rich in both cholesterol esters and triglycerides, reflecting their transitional nature as they are either taken up by the liver or further metabolized into LDL.
Metabolic Role and Lipoprotein Classification
Section titled “Metabolic Role and Lipoprotein Classification”IDL plays a crucial role in the endogenous lipid transport pathway, serving as a remnant of VLDL metabolism and a precursor to LDL. After VLDL releases much of its triglyceride content, it becomes an IDL particle, which contains a higher proportion of cholesterol relative to triglycerides compared to VLDL. This position places IDL centrally within the classification of lipoproteins by density, where VLDL is the least dense, followed by IDL, then LDL, and finally high-density lipoprotein (HDL) as the most dense. The metabolic fate of IDL, whether it is cleared from circulation or converted to LDL, significantly influences overall lipid profiles and cardiovascular risk.
Measurement Considerations and Clinical Significance
Section titled “Measurement Considerations and Clinical Significance”The concentration of cholesterol in IDL can be assessed through various laboratory methods, though it is not routinely measured in standard lipid panels. Direct measurement often involves ultracentrifugation or specific immunoassay techniques, while some approaches estimate IDL cholesterol indirectly as part of non-HDL cholesterol. Clinically, elevated IDL cholesterol is recognized as a component of dyslipidemia, contributing to the overall burden of atherogenic lipoproteins. Its presence signifies an imbalance in lipoprotein metabolism, and it is considered an independent risk factor for atherosclerosis, often reflecting impaired VLDL catabolism or increased production of VLDL remnants.
Genetic Predisposition and Inherited Influences
Section titled “Genetic Predisposition and Inherited Influences”Genetic factors are fundamental determinants of an individual’s cholesterol in IDL levels, contributing significantly to inter-individual variability. Inherited genetic variants, ranging from common polymorphisms that contribute to a polygenic risk score to rare Mendelian forms, can profoundly influence the synthesis, metabolism, and clearance of intermediate-density lipoproteins. These genetic differences often impact the efficiency of enzymes involved in lipid processing, the activity of lipoprotein receptors, and the structural integrity of lipoproteins themselves, thereby leading to diverse IDL cholesterol profiles. Furthermore, complex gene-gene interactions can modulate the overall genetic predisposition, where the effect of one genetic variant might be influenced or modified by the presence of others, leading to a nuanced genetic architecture for cholesterol in IDL.
Environmental, Lifestyle, and Gene-Environment Interactions
Section titled “Environmental, Lifestyle, and Gene-Environment Interactions”Environmental and lifestyle factors play a crucial role in shaping cholesterol in IDL levels, often interacting dynamically with an individual’s inherent genetic makeup. Dietary patterns, including the intake of saturated and trans fats, cholesterol, and refined carbohydrates, directly impact lipoprotein synthesis and catabolism. Other lifestyle choices such as physical activity levels, smoking status, and alcohol consumption are also significant contributors, influencing metabolic pathways that regulate IDL metabolism and clearance. Beyond individual behaviors, broader environmental exposures, socioeconomic factors, and geographic influences can further modify IDL cholesterol levels through their effects on diet, access to healthy resources, and overall lifestyle choices. These factors often trigger or mitigate genetic predispositions, demonstrating how specific genetic variants can confer differential susceptibility to environmental influences, leading to varied IDL responses to similar exposures.
Developmental, Epigenetic, and Acquired Influences
Section titled “Developmental, Epigenetic, and Acquired Influences”The trajectory of cholesterol in IDL levels is also shaped by developmental and epigenetic factors, which exert long-lasting effects on metabolic programming. Early life influences, such as prenatal nutrition and maternal health, can induce epigenetic modifications like DNA methylation and histone modifications, thereby altering gene expression patterns that persist into adulthood and affect lipid metabolism. These early life experiences can program an individual’s metabolic profile, influencing how they process lipoproteins later in life. Additionally, various acquired factors contribute to IDL cholesterol variability, including the presence of comorbidities such as type 2 diabetes and metabolic syndrome, certain medication effects that interfere with lipid pathways, and age-related physiological changes that alter lipoprotein kinetics and clearance efficiency. These diverse influences can independently or synergistically impact IDL cholesterol levels throughout an individual’s lifespan.
Biological Background
Section titled “Biological Background”Lipoprotein Metabolism and IDL Dynamics
Section titled “Lipoprotein Metabolism and IDL Dynamics”Cholesterol is transported throughout the body within lipoprotein particles, which are crucial for energy distribution and cellular processes. Very Low-Density Lipoproteins (VLDL) are synthesized in the liver and released into circulation, carrying triglycerides and cholesterol to peripheral tissues. As VLDL particles circulate, they are acted upon by lipoprotein lipase (LPL), an enzyme primarily found on the surface of endothelial cells in adipose tissue and muscle, which hydrolyzes triglycerides and converts VLDL into Intermediate-Density Lipoproteins (IDL).[2]IDL particles are thus transient intermediates in the lipoprotein cascade, characterized by a reduced triglyceride content and an increased proportion of cholesterol esters compared to VLDL.
The fate of IDL is critical for overall cholesterol homeostasis, as they can either be cleared directly by the liver or further metabolized into Low-Density Lipoproteins (LDL). Hepatic lipase (HL), an enzyme predominantly expressed in the liver, plays a significant role in hydrolyzing the remaining triglycerides and phospholipids in IDL, facilitating their conversion to LDL. Both IDL and LDL particles are recognized and internalized by the Low-Density Lipoprotein Receptor (LDLR), primarily in the liver, which is a key mechanism for clearing cholesterol-rich lipoproteins from the circulation. [3] The balance between IDL conversion to LDL and direct hepatic uptake of IDL profoundly influences circulating IDL levels.
Regulation of Cholesterol Homeostasis
Section titled “Regulation of Cholesterol Homeostasis”The body employs intricate regulatory networks to maintain cholesterol balance, with the liver serving as the central organ for cholesterol synthesis, uptake, and secretion. The expression of the LDLRgene, which dictates the rate of lipoprotein clearance, is tightly controlled by transcription factors such as Sterol Regulatory Element-Binding Proteins (SREBP). When intracellular cholesterol levels are low, SREBP proteins are activated, leading to increased transcription of LDLR and enzymes involved in cholesterol synthesis, thereby increasing cholesterol uptake and production. [4] This feedback loop ensures that cells can acquire cholesterol as needed while preventing excessive accumulation.
Another critical regulatory protein is Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), which post-translationally regulates LDLR levels. PCSK9 binds to the LDLRon the cell surface and targets it for lysosomal degradation, thus reducing the number of available receptors for lipoprotein uptake.[5] Genetic variations in PCSK9 can alter its activity, leading to changes in LDLR abundance and consequently influencing circulating levels of IDL and LDL cholesterol. Hormonal signals and dietary factors also contribute to the complex interplay that governs the synthesis and catabolism of lipoproteins, impacting systemic cholesterol levels.
Genetic Influences on IDL Cholesterol
Section titled “Genetic Influences on IDL Cholesterol”Genetic mechanisms play a substantial role in determining an individual’s cholesterol in IDL levels and overall lipid profile. Variations within theAPOE gene are particularly influential, as the APOE protein is a component of VLDL, IDL, and chylomicrons, acting as a ligand for the LDLR and other receptors. Different APOEisoforms (e.g., E2, E3, E4), arising from common genetic variants, exhibit distinct binding affinities for lipoprotein receptors, affecting the clearance rate of IDL and VLDL remnants.[6] For instance, the APOEE2 allele is often associated with impaired remnant clearance and higher triglyceride levels, while the E4 allele is linked to higher LDL cholesterol.
Beyond APOE, genetic variations in other genes encoding key enzymes and receptors involved in lipoprotein metabolism can also impact IDL cholesterol. For example, polymorphisms inLPL or HL genes can alter the activity of these enzymes, thereby affecting the conversion of VLDL to IDL, and IDL to LDL. Similarly, genetic variants in the LDLR gene itself can lead to reduced receptor function or expression, impairing the liver’s ability to clear IDL and LDL from the bloodstream. [7] These genetic predispositions contribute to inter-individual variability in IDL cholesterol levels and can influence an individual’s susceptibility to dyslipidemia.
Pathophysiological Implications of IDL Cholesterol
Section titled “Pathophysiological Implications of IDL Cholesterol”Elevated levels of cholesterol in IDL are increasingly recognized as an independent risk factor for cardiovascular disease, particularly atherosclerosis. IDL particles, being cholesterol-rich and having a longer residence time in circulation compared to VLDL, are considered pro-atherogenic. They can penetrate the arterial wall and become trapped within the subendothelial space, where they undergo oxidative modifications.[8] These modified IDL particles are then readily taken up by macrophages, leading to foam cell formation, a hallmark event in the initiation and progression of atherosclerotic plaques.
The accumulation of IDL cholesterol represents a disruption in normal homeostatic processes, indicating impaired remnant lipoprotein clearance. This dysregulation contributes to systemic inflammation and endothelial dysfunction, further promoting the development of atherosclerosis. High IDL cholesterol levels are often observed in individuals with metabolic syndrome, type 2 diabetes, and familial dysbetalipoproteinemia, highlighting their role in complex metabolic disorders and their significant contribution to increased cardiovascular risk. Effective management of IDL cholesterol is therefore crucial in mitigating the progression of these pathophysiological conditions.[9]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Lipoprotein Metabolism and Flux Control
Section titled “Lipoprotein Metabolism and Flux Control”The metabolism of cholesterol in Intermediate-Density Lipoproteins (IDL) is a critical juncture in the broader lipoprotein cascade, bridging very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) metabolism. IDL particles are formed in the circulation as VLDL loses triglycerides through the action of lipoprotein lipase (LPL) in peripheral tissues. This process enriches the particle with cholesterol esters and reduces its triglyceride content, transforming it into an IDL, which still contains bothApoB-100 and ApoE. [1] The hepatic lipase (HL) enzyme further acts on IDL in the liver, hydrolyzing remaining triglycerides and phospholipids, which is a key step in converting IDL to LDL. The precise balance of these enzymatic activities dictates the flux of cholesterol through IDL, influencing the overall systemic lipid profile.
Receptor-Mediated Uptake and Signaling
Section titled “Receptor-Mediated Uptake and Signaling”The liver plays a central role in clearing IDL from circulation, primarily through receptor-mediated endocytosis. The low-density lipoprotein receptor (LDLR) and the LDL receptor-related protein 1 (LRP1) recognize the ApoE component on IDL, facilitating its binding and subsequent internalization into hepatocytes. [3]This receptor-ligand interaction initiates intracellular signaling cascades that regulate cellular cholesterol levels. Upon internalization, the IDL particles are delivered to endosomes and lysosomes, where cholesterol esters are hydrolyzed, releasing free cholesterol. This free cholesterol then serves as a signal, activating or repressing transcription factors like the sterol regulatory element-binding proteins (SREBP) to maintain cellular cholesterol homeostasis through feedback loops. [10]
Hepatic Processing and Regulatory Mechanisms
Section titled “Hepatic Processing and Regulatory Mechanisms”Once IDL-derived cholesterol is taken up by hepatocytes, it is integrated into the cell’s metabolic pool, influencing several regulatory mechanisms. The availability of intracellular cholesterol directly impacts the gene expression of enzymes involved in cholesterol synthesis, such as HMG-CoA reductase, and the LDLR itself, largely mediated by SREBP transcription factors. When intracellular cholesterol is high, SREBP activity is suppressed, leading to decreased cholesterol synthesis and LDLR expression. [4] Furthermore, protein modification, such as ubiquitination of LDLR by PCSK9, can target the receptor for degradation, thereby reducing IDL uptake and increasing circulating IDL levels. Allosteric control mechanisms also regulate key enzymes in cholesterol metabolism, ensuring a tightly controlled cellular response to cholesterol fluctuations.
Inter-organ Crosstalk and Systemic Regulation
Section titled “Inter-organ Crosstalk and Systemic Regulation”The metabolism of cholesterol in IDL is not confined to the liver but is part of a complex network involving multiple organs and circulating factors, demonstrating significant systems-level integration. Adipose tissue and muscle contribute to VLDL triglyceride hydrolysis, indirectly affecting IDL formation, while the liver is the primary site of IDL catabolism and LDL production. Hormones such as insulin and thyroid hormones can modulate the activity of lipoprotein lipase and hepatic lipase, thereby influencing the rate of VLDL-to-IDL and IDL-to-LDL conversion.[11] This intricate pathway crosstalk ensures that systemic lipid levels are maintained within a narrow physiological range, highlighting the hierarchical regulation necessary for overall metabolic health.
Dysregulation and Disease Implications
Section titled “Dysregulation and Disease Implications”Dysregulation in the pathways governing cholesterol in IDL can have significant disease-relevant mechanisms, particularly in the development of atherosclerosis. Elevated levels of IDL cholesterol (IDL-C) are considered atherogenic, as IDL particles can penetrate the arterial wall and contribute to plaque formation. Genetic variations, such as polymorphisms in theAPOE gene (e.g., APOE rs7412 , APOE rs429358 ) or mutations affecting LDLR function, can impair IDL clearance, leading to its accumulation in the bloodstream. [6] Compensatory mechanisms may attempt to restore lipid homeostasis, such as upregulation of LDLRin response to low intracellular cholesterol, but persistent dysregulation often necessitates therapeutic interventions targeting IDL metabolism, including lifestyle modifications and lipid-lowering medications that can enhance IDL clearance or reduce its production.
Clinical Relevance
Section titled “Clinical Relevance”Assessing Cardiovascular Risk and Disease Progression
Section titled “Assessing Cardiovascular Risk and Disease Progression”Cholesterol in intermediate-density lipoprotein (IDL) is increasingly recognized as a significant independent risk factor for atherosclerotic cardiovascular disease (CVD) and its complications. Elevated levels of cholesterol in IDL indicate a higher burden of atherogenic particles that contribute to plaque formation and progression within arterial walls, thereby increasing the likelihood of future cardiac events such as myocardial infarction and stroke.[12]Its prognostic value extends beyond traditional lipid markers like LDL-C, offering a more refined prediction of adverse cardiovascular outcomes and identifying individuals at heightened risk despite seemingly controlled conventional lipid profiles.[13]Monitoring cholesterol in IDL can therefore guide the implementation of more aggressive primary or secondary prevention strategies, tailored to the individual’s specific atherogenic particle burden.
Diagnostic Utility and Therapeutic Management
Section titled “Diagnostic Utility and Therapeutic Management”Measurements of cholesterol in IDL offer valuable diagnostic utility, particularly for refining cardiovascular risk assessment in specific patient populations. This includes individuals with metabolic syndrome, type 2 diabetes, or those exhibiting residual risk despite achieving target LDL-C levels, where elevated IDL cholesterol often contributes significantly to overall atherogenicity.[14] Its assessment can also inform treatment selection, guiding clinicians in choosing appropriate lipid-lowering therapies, such as statins or PCSK9 inhibitors, that effectively target the broader spectrum of atherogenic lipoproteins beyond LDL-C alone. [15]Furthermore, monitoring cholesterol in IDL can serve as a valuable strategy for evaluating treatment response, ensuring that interventions are not only reducing LDL-C but also adequately addressing other pro-atherogenic particles to achieve comprehensive lipid management.
Comorbidities and Overlapping Phenotypes
Section titled “Comorbidities and Overlapping Phenotypes”Elevated cholesterol in IDL is frequently associated with a range of metabolic comorbidities, reflecting complex underlying pathophysiological mechanisms. These include conditions such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD), where dyslipidemia often features an accumulation of IDL particles due to impaired triglyceride metabolism and altered lipoprotein kinetics.[16]Understanding the interplay between cholesterol in IDL and these associated conditions is crucial for patients presenting with overlapping metabolic phenotypes, as it provides insights into disease mechanisms and helps guide comprehensive management strategies. Addressing elevated IDL cholesterol in these contexts can contribute to a more holistic approach to patient care, potentially mitigating not only cardiovascular risk but also influencing the progression of related metabolic disorders.
References
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