Total Lipids In Hdl
Background
Section titled “Background”High-density lipoprotein cholesterol (HDL-C), often referred to as “good cholesterol,” is a crucial component of serum lipids, playing a vital role in lipid metabolism and cardiovascular health. Along with low-density lipoprotein cholesterol (LDL-C) and triglycerides, HDL-C levels are significant determinants of cardiovascular disease and are associated with morbidity.[1] The concentration of these circulating lipid levels is highly heritable, with genetic factors contributing substantially to individual variation. [1]
Biological Basis
Section titled “Biological Basis”The biological basis of HDL-C levels involves a complex interplay of numerous genes and their encoded proteins that regulate lipid metabolism. [1] Genome-wide association (GWA) studies have been instrumental in identifying genetic loci influencing HDL-C concentrations. These studies have implicated genes such as _ABCA1_, _CETP_, _LIPC_, _LIPG_, _GALNT2_, and a region including _APOA5-APOA4-APOC3-APOA1_ as key determinants of HDL cholesterol levels. [1] For example, variants near _CETP_, _LPL_, and _LIPC_ have shown strong associations with HDL cholesterol levels. [2] Additionally, the expression of genes like _PLTP_ has been directly linked to HDL cholesterol levels, where higher _PLTP_ transcript levels are associated with higher HDL cholesterol. [3] While many common variants have been identified, they currently explain only a small fraction of the total variation in lipid concentrations within the population. [1]
Clinical Relevance
Section titled “Clinical Relevance”Given their integral role in cardiovascular health, the study of total lipids in HDL has significant clinical relevance. Abnormal HDL cholesterol levels are a known risk factor for cardiovascular disease. Genetic profiling using scores derived from associated lipid genes can provide explanatory value and marginally improve the prediction of coronary heart disease risk, especially when combined with traditional clinical risk factors.[1] Furthermore, these genetic insights can help identify individuals at higher risk, as the proportion of individuals exceeding clinical thresholds for ‘low’ HDL cholesterol increases with specific genetic risk scores. [3] Measurements of HDL cholesterol are typically performed using fasting blood samples to ensure accurate assessment. [3]
Social Importance
Section titled “Social Importance”The pervasive impact of cardiovascular disease on global health underscores the social importance of understanding the genetic underpinnings of total lipids in HDL. Research into these genetic determinants contributes to a broader public health goal of preventing and managing cardiovascular conditions. By uncovering the genetic architecture influencing HDL-C levels, scientists and clinicians can develop more targeted prevention strategies, personalized risk assessments, and potentially novel therapeutic interventions. This knowledge empowers individuals and healthcare providers to make informed decisions regarding lifestyle, screening, and treatment, ultimately striving to reduce the burden of cardiovascular disease on society.
Limitations
Section titled “Limitations”The comprehensive genetic studies on total lipids in HDL, while providing significant insights into their polygenic architecture, are subject to several limitations that warrant careful consideration in interpreting their findings and planning future research.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Despite the utilization of large meta-analyses, encompassing tens of thousands of individuals in discovery and replication stages [3] the studies acknowledge that even larger samples and enhanced statistical power are necessary for the discovery of additional sequence variants. [3]This implies that many genetic influences on total lipids in HDL may still remain undetected due to insufficient power. The currently identified common loci explain only a small fraction of the total variation in HDL concentrations, for instance, 9.3% for HDL cholesterol[3] indicating modest individual effect sizes that require rigorous validation.
Although robust replication analyses were conducted, the potential for effect-size inflation, particularly for variants with smaller influences, cannot be entirely dismissed without further independent validation across even more diverse cohorts. Additionally, while some studies were designed as population-based cohorts to mitigate ascertainment bias[1]others included participants ascertained for specific disease states like diabetes.[2] Such heterogeneity in cohort selection could introduce subtle biases, affecting the generalizability of certain associations and their estimated population-level impact.
Generalizability and Phenotype Heterogeneity
Section titled “Generalizability and Phenotype Heterogeneity”A significant limitation is the predominant reliance on participants of European ancestry across a majority of the contributing cohorts. [4] While a multiethnic sample including Chinese, Malays, and Asian Indians was incorporated in some replication efforts [3]this limited representation constrains the direct generalizability of the findings to other global populations. The genetic underpinnings of total lipids in HDL are known to vary across different ancestral backgrounds, necessitating extensive investigation in non-European populations to fully understand their global architecture.
Furthermore, inconsistencies in phenotype measurement and covariate adjustment exist across studies. Variations include different fasting protocols (e.g., minimum 4-hour fast vs. strict overnight fast) and differing approaches to handling individuals on lipid-lowering therapy. [3] For example, some cohorts excluded individuals on therapy, while others, particularly older studies, did not. [3]These methodological disparities can introduce variability or unaddressed confounding, thereby affecting the precision and comparability of HDL measurements and the associated genetic signals. The observation of sex-specific effects for some loci further highlights the complexity, suggesting that a simple additive model may not fully capture the genetic influences on total lipids in HDL across genders.[1]
Unexplained Heritability and Complex Interactions
Section titled “Unexplained Heritability and Complex Interactions”Despite the identification of numerous statistically significant loci, the cumulative contribution of these genetic variants explains only a modest fraction of the observed variation in total lipids in HDL (e.g., 9.3% for HDL cholesterol).[3] This substantial “missing heritability” suggests that a large proportion of the genetic determinants remain undiscovered, potentially including rare variants, structural variations, or more complex epistatic interactions that were not fully captured by the common variant genome-wide association study design.
Moreover, the studies primarily focused on identifying genetic associations, with covariate adjustments limited to basic demographics such as age, sex, and population stratification. [3]A detailed exploration of environmental factors (e.g., diet, physical activity, lifestyle) and their intricate gene–environment interactions was not extensively undertaken. These unmeasured or unmodeled environmental influences and their synergistic or antagonistic effects with genetic predispositions could significantly modulate total lipids in HDL levels, representing a critical knowledge gap in elucidating the complete etiology of polygenic dyslipidemia. The genetic profiles identified, while informative, are acknowledged as “far from complete,” underscoring the ongoing need for further characterization of genetic and environmental factors influencing serum lipids.[1]
Variants
Section titled “Variants”Genetic variations play a crucial role in determining an individual’s lipid profile, including the concentration and composition of total lipids in high-density lipoprotein (HDL). These variants, primarily single nucleotide polymorphisms (SNPs), are located within or near genes that govern various aspects of lipid metabolism, from lipoprotein synthesis and remodeling to fatty acid desaturation and cholesterol transport. Understanding these genetic influences helps elucidate the complex mechanisms underlying dyslipidemia.
Several gene variants significantly impact HDL cholesterol, a key component of total HDL lipids, and related lipid traits. For instance, the CETP(Cholesteryl Ester Transfer Protein) gene encodes a protein that facilitates the transfer of cholesteryl esters from HDL to other lipoproteins, influencing HDL particle size and concentration. Variants nearCETP, such as rs821840 , are hypothesized to modulate this activity, affecting total lipids within HDL particles. [2] Similarly, variations associated with the LIPCgene, which encodes hepatic lipase, can alter the hydrolysis of phospholipids and triglycerides in HDL, impacting its remodeling and maturation. The SNPrs10468017 is located near LIPC and has been linked to HDL cholesterol levels, with rs633695 also influencing this pathway. [2] The PLTP (Phospholipid Transfer Protein) gene plays a role in exchanging phospholipids between lipoproteins, and a variant like rs6065904 could modify this exchange, altering the lipid composition of HDL. The ALDH1A2 gene, involved in retinoic acid synthesis, can also indirectly influence overall lipid metabolism, affecting HDL through variants like rs11071373 . [4] The gene HERPUD1, located near CETP, is involved in endoplasmic reticulum stress, a process that can broadly influence cellular lipid handling and, consequently, HDL integrity and function.
Other gene variants primarily influence low-density lipoprotein (LDL) cholesterol, but these changes can cascade to affect HDL. TheCELSR2 gene region, which includes the variant rs12740374 , is strongly associated with LDL cholesterol levels. [3] While CELSR2 affects LDL, alterations in LDL metabolism can indirectly influence HDL by altering lipid exchange dynamics and overall reverse cholesterol transport. Variants in the LDLR(Low-Density Lipoprotein Receptor) gene, such asrs73015021 , affect the clearance of LDL from the bloodstream. Impaired LDL clearance can alter the availability of lipids for transfer to HDL and impact general lipid homeostasis. [2] The APOBgene, encoding a key structural protein of LDL and other lipoproteins, is associated with LDL and triglyceride levels, and variants likers562338 can impact the assembly and catabolism of these particles. These changes can subsequently influence HDL by altering the pool of lipids available for exchange. [2] Additionally, SMARCA4 and TDRD15 are genes involved in chromatin remodeling and epigenetic regulation, respectively, and variants in these regions can broadly affect gene expression pathways, including those involved in lipid metabolism, indirectly influencing HDL.
Beyond direct lipoprotein metabolism, genes involved in fatty acid synthesis and other cellular processes also affect total lipids in HDL. TheFADS1 and FADS2 genes encode desaturase enzymes critical for synthesizing polyunsaturated fatty acids (PUFAs). Variants such as rs174564 can alter an individual’s fatty acid profile, which in turn affects the lipid composition and fluidity of lipoprotein particles, including HDL.[5] The TOMM40 gene, associated with rs1160983 , plays a role in mitochondrial protein import and cellular energy metabolism. Disruptions here could alter lipid oxidation and cellular lipid availability, indirectly impacting the assembly and remodeling of HDL particles. The BCAM (Basal Cell Adhesion Molecule) gene, linked to rs118147862 , can influence lipid metabolism through its roles in cell signaling and inflammation, which are known to interact with lipoprotein dynamics and contribute to the overall lipid landscape of HDL.[6]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Definition and Biological Significance of HDL Cholesterol
Section titled “Definition and Biological Significance of HDL Cholesterol”High-density lipoprotein (HDL) cholesterol refers to the cholesterol carried by high-density lipoprotein particles, commonly known as “good cholesterol” due to its inverse association with cardiovascular disease risk. HDL particles are a complex class of lipoproteins involved in reverse cholesterol transport, a pathway that removes excess cholesterol from peripheral tissues and returns it to the liver for excretion or reprocessing. This crucial function helps to prevent the accumulation of cholesterol in arterial walls, thereby protecting against the development of atherosclerosis, the underlying pathology of coronary artery disease (CAD).[2]Specifically, research indicates that each 1% increase in HDL cholesterol concentrations is associated with an approximate 2% reduction in the risk of coronary heart disease.[2]HDL cholesterol levels are considered an important determinant of cardiovascular health and are broadly studied as a key lipid trait in human populations.[1]
Measurement Approaches and Operational Definitions
Section titled “Measurement Approaches and Operational Definitions”The determination of HDL cholesterol concentration typically involves measuring it in fasting blood samples, which are collected after a specified fasting period, often at least four hours, with common practice extending to six hours or more. [5]Lipid concentrations, including HDL cholesterol, are generally measured using standard enzymatic methods. For research purposes, particularly in genome-wide association studies, HDL cholesterol levels are frequently adjusted for various confounding factors such as age, age squared, sex, and population substructure, often by creating sex-specific residual lipoprotein concentrations.[3] Individuals who have not fasted or are on lipid-lowering medication are typically excluded from analyses to ensure the accuracy and comparability of lipid trait data. [5]
Clinical Classification and Risk Thresholds
Section titled “Clinical Classification and Risk Thresholds”Clinical guidelines, such as those established by the National Cholesterol Education Program, define normal ranges for HDL cholesterol to categorize individuals and assess their cardiovascular risk.[7] A normal range for HDL cholesterol is considered to be between 40 and 80 mg/dl. [7]Levels below this range are generally considered undesirable and indicative of an increased risk for cardiovascular disease, while higher concentrations are associated with a decreased risk.[2]These established thresholds serve as critical diagnostic criteria and inform clinical management strategies aimed at reducing morbidity and mortality associated with adverse lipid profiles.[1]
Causes of Total Lipids in HDL
Section titled “Causes of Total Lipids in HDL”Total lipids in high-density lipoprotein (HDL) are influenced by a complex interplay of genetic, lifestyle, and physiological factors. Research indicates a high degree of heritability for circulating lipid levels, but also highlights the significant contribution of environmental influences and their interactions.
Genetic Architecture of HDL Lipid Levels
Section titled “Genetic Architecture of HDL Lipid Levels”The levels of total lipids in HDL are strongly influenced by genetic factors, a characteristic well-established through studies showing high heritability.[1]This genetic predisposition includes both rare variants with major effects, leading to Mendelian forms of dyslipidemias, and a vast array of common single nucleotide polymorphisms (SNPs) with smaller, additive effects.[1] Genome-wide association studies (GWAS) have identified numerous gene loci implicated in HDL regulation, including ABCA1, CETP, LIPC, LPL, LIPG, GALNT2, and the APOA5-APOA4-APOC3-APOA1 cluster [1], [3]. [2] For instance, variants near GALNT2 in the 1q42 locus have been associated with HDL [3] suggesting a role for O-linked glycosylation in HDL metabolism [3].
While specific common variants, such as rs289714 in CETP and rs2070895 in LIPC, show strong associations with HDL levels [3] these individually or combined only explain a fraction of the variation in the population, currently around 9.3% for HDL cholesterol [3]. This indicates a polygenic architecture where many variants, often acting in concert, contribute to the overall lipid profile. [8] The remaining unexplained heritability suggests the involvement of a larger number of common variants of small effect, rare variants with larger effects, and complex gene-gene or gene-environment interactions yet to be fully characterized. [2]
Lifestyle and Environmental Modulators
Section titled “Lifestyle and Environmental Modulators”Lifestyle and environmental factors play a crucial role in modulating total lipids in HDL. Dietary habits are a primary determinant, with dietary changes recognized as a key population-level strategy for preventing adverse lipid profiles.[1]The composition of an individual’s diet can directly influence the synthesis, metabolism, and clearance of lipoproteins, thereby affecting HDL levels. Body Mass Index (BMI), a measure reflecting lifestyle and energy balance, also serves as a significant predictor of lipid levels, with studies frequently using it as a covariate to understand its comparative effect on lipid traits.[1]
Although detailed mechanisms of specific environmental exposures beyond diet and BMI are less elaborated in the available studies, it is understood that broad environmental contexts contribute to the overall variability in lipid concentrations. These factors, alongside genetic predispositions, shape an individual’s risk for dyslipidemia. However, the exact interplay between specific environmental triggers and their impact on HDL lipid levels often necessitates further investigation to clarify their precise contributions.
Biological and Clinical Factors
Section titled “Biological and Clinical Factors”Beyond genetics and lifestyle, a range of biological and clinical factors contributes to the variability in total lipids in HDL. Age is a significant modulator; studies consistently adjust for age and age squared in analyses, acknowledging its influence on lipid concentrations[3]. Furthermore, sex-specific differences in lipid metabolism are observed, prompting researchers to create sex-specific models and test for distinct effects between males and females [1], [3].
Comorbidities also play an important role, with conditions like type 2 diabetes frequently enriching study samples due to their strong association with altered lipid profiles [1], [3]. These underlying health conditions can independently or synergistically affect HDL lipid levels through various physiological pathways. Additionally, medications, particularly lipid-lowering therapies such as statins, are crucial clinical factors; their use is a key strategy in preventing cardiovascular risk and must be accounted for in studies to accurately assess inherent lipid levels[1], [3].
Biological Background
Section titled “Biological Background”The Dynamic Nature of HDL and Key Regulatory Proteins
Section titled “The Dynamic Nature of HDL and Key Regulatory Proteins”High-density lipoprotein (HDL) is a complex particle integral to lipid metabolism, particularly known for its role in reverse cholesterol transport. The total lipid content of HDL is dynamically regulated by specific proteins that influence its formation, remodeling, and overall composition.[9] Key biomolecules such as Apolipoprotein AI (APOA1) serve as the primary structural component of HDL, while Phospholipid Transfer Protein (PLTP) facilitates the exchange of phospholipids and other lipids between lipoproteins. [9] Experimental studies involving transgenic mice expressing human PLTP and APOA1 have demonstrated an increase in prebeta-HDL, APOA1, and phospholipid levels, illustrating the direct impact of these proteins on HDL’s lipid profile and structural integrity. [9]
Genetic Determinants of HDL Lipid Levels
Section titled “Genetic Determinants of HDL Lipid Levels”The individual variability in total lipids within HDL is significantly influenced by genetic factors, with common variants at numerous loci contributing to the polygenic nature of dyslipidemia. [10] Specific genes, through their expression patterns and regulatory elements, play a crucial role in determining an individual’s HDL characteristics. For instance, the gene encoding Phospholipid Transfer Protein (PLTP) is a key genetic determinant, as targeted mutations in PLTPcan lead to a marked reduction in overall high-density lipoprotein levels.[11] Similarly, polymorphisms within the promoter region of the Hepatic Lipase (LIPC) gene, such as the -514C->T variant, are known to influence plasma lipid profiles, thereby highlighting the genetic regulation of enzymes involved in HDL metabolism. [12]
Enzymatic Regulation and Cellular Metabolism of HDL Lipids
Section titled “Enzymatic Regulation and Cellular Metabolism of HDL Lipids”The intricate process of HDL lipid metabolism relies heavily on the coordinated actions of various enzymes and transfer proteins at a cellular level. Hepatic Lipase (LIPC) is an enzyme primarily responsible for the hydrolysis of phospholipids and triglycerides within lipoproteins, including HDL, thereby influencing the particle size and lipid load of HDL.[12] Genetic variations, such as polymorphisms in the LIPC promoter, can alter the enzyme’s expression and activity, leading to changes in plasma lipid levels. [12] Concurrently, PLTPmediates the transfer of phospholipids and cholesterol esters between different lipoprotein classes, a vital cellular function that continuously remodels HDL particles and regulates their lipid composition, which in turn affects their ability to perform reverse cholesterol transport.[9]
Systemic Influences and Pathophysiological Relevance of HDL Lipids
Section titled “Systemic Influences and Pathophysiological Relevance of HDL Lipids”Disruptions in the normal homeostasis of total lipids in HDL have systemic consequences and are closely associated with pathophysiological processes such as dyslipidemia, a condition characterized by abnormal lipid profiles.[10]While genetic predispositions set a baseline for an individual’s lipid metabolism, environmental and lifestyle factors can also significantly modulate these levels. For example, dietary interventions, specifically the consumption of fish oils, have been shown to reduce plasma lipids, lipoproteins, and apoproteins in patients suffering from hypertriglyceridemia.[13]This indicates that the total lipid content of HDL, a key lipoprotein, can be influenced by broader systemic responses to dietary components, highlighting the complex interplay between genetic susceptibility, metabolic regulation, and external factors in maintaining lipid health.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”HDL Biogenesis and Initial Lipid Association
Section titled “HDL Biogenesis and Initial Lipid Association”The initial formation of high-density lipoprotein (HDL) particles, which directly impacts their total lipid content, begins with the primary apolipoprotein,APOA1. APOA1 serves as the structural scaffold around which nascent HDL particles are assembled. This crucial step involves the association of phospholipids with APOA1, leading to the formation of discoidal prebeta-HDL. Research involving mice expressing human APOA1 transgenes showed an increase in prebeta-HDL, apolipoprotein AI, and phospholipids [4] demonstrating APOA1’s fundamental role in initiating HDL biosynthesis and its initial lipid loading. This process represents a critical aspect of metabolic regulation, establishing the foundation for subsequent lipid accumulation within the HDL particle.
Dynamic Remodeling of HDL Lipid Content
Section titled “Dynamic Remodeling of HDL Lipid Content”The total lipid content of HDL particles is dynamically regulated through the actions of various enzymes and lipid transfer proteins. Phospholipid transfer protein (PLTP) is a key player in this remodeling process, facilitating the transfer of phospholipids between lipoproteins and thereby influencing HDL size and lipid composition. Studies have shown that increased expression of humanPLTP in mice, alongside human APOA1, leads to elevated levels of phospholipids within prebeta-HDL. [4] Conversely, a targeted mutation in the PLTPgene results in a significant reduction in overall high-density lipoprotein levels[11] highlighting PLTP’s essential role in maintaining HDL’s structural integrity and its lipid load, which is a critical point of flux control in HDL metabolism. Similarly, hepatic lipase (LIPC) contributes to the modification of HDL’s lipid profile through its hydrolytic activity on triglycerides and phospholipids, leading to changes in particle density and total lipid content. This enzymatic activity is integral to HDL catabolism and the overall metabolic regulation of its composition.
Genetic and Transcriptional Control of HDL Metabolism
Section titled “Genetic and Transcriptional Control of HDL Metabolism”Genetic variations exert significant influence over the regulatory mechanisms governing the total lipids in HDL. A notable example is a polymorphism in the promoter region of theLIPC gene, specifically the -514C>T variant, which has been linked to variations in plasma lipid levels. [12] This illustrates how gene regulation at the transcriptional level, modulated by promoter region polymorphisms, can impact the expression and activity of enzymes crucial for HDL remodeling, thereby directly affecting its lipid content. Such genetic variants are key determinants of metabolic flux and contribute to the individual variability observed in HDL lipid profiles. Furthermore, the contribution of common variants at numerous other genetic loci to polygenic dyslipidemia [3] underscores the widespread gene regulation and intricate network interactions that collectively shape overall lipid metabolism, consequently influencing total lipids within HDL.
Interplay with Systemic Lipid Homeostasis and Therapeutic Targets
Section titled “Interplay with Systemic Lipid Homeostasis and Therapeutic Targets”The total lipid content of HDL particles is deeply intertwined with broader systemic lipid homeostasis and extensive pathway crosstalk. Dietary interventions, such as the consumption of fish oils, can significantly reduce plasma lipids, lipoproteins, and apoproteins [13] indicating that exogenous factors can profoundly influence the metabolic environment impacting HDL function. This demonstrates how overall energy metabolism and the flux of lipids throughout the body can directly or indirectly affect the lipid load of HDL, representing a form of hierarchical regulation and systems-level integration. Dysregulation within these interconnected pathways can lead to altered HDL lipid profiles, making key components like PLTP or LIPCactivity promising therapeutic targets for managing dyslipidemia and improving cardiovascular health.
Clinical Relevance
Section titled “Clinical Relevance”Risk Assessment and Prognostic Implications
Section titled “Risk Assessment and Prognostic Implications”HDL cholesterol levels serve as a critical indicator in assessing cardiovascular disease risk, with high concentrations consistently associated with a reduced incidence of coronary artery disease (CAD).[2]Research suggests that even a 1% increase in HDL cholesterol concentrations can reduce the risk of coronary heart disease by approximately 2%, underscoring its significant prognostic value in predicting clinical outcomes and disease progression.[2]While common genetic variations influencing HDL cholesterol explain a modest portion of its population variability, genetic risk scores incorporating these variants can offer marginal improvements in cardiovascular disease prediction beyond traditional clinical risk factors, aiding in early identification of individuals predisposed to dyslipidemias and guiding preventive strategies.[1]
Clinical Utility and Management Strategies
Section titled “Clinical Utility and Management Strategies”In clinical practice, the diagnostic utility of HDL cholesterol levels is firmly established, with National Cholesterol Education Program guidelines defining normal ranges typically between 40 and 80 mg/dl. [7]Monitoring HDL cholesterol, along with other key lipid parameters like total and LDL cholesterol, is standard for comprehensive cardiovascular risk assessment, influencing treatment selection and the implementation of management protocols. Although the added predictive value of genetic scores for incident coronary heart disease may be limited when circulating lipid levels are already considered, understanding the genetic determinants of HDL cholesterol contributes to the broader framework of lipid metabolism and disease pathophysiology, potentially informing future personalized medicine approaches.[1]Current population-level prevention efforts rely on routine lipid screening, dietary modifications, and pharmacotherapy, such as statins, to manage circulating lipid levels and mitigate cardiovascular risk.[1]
Genetic Determinants and Associated Comorbidities
Section titled “Genetic Determinants and Associated Comorbidities”HDL cholesterol concentrations are recognized as highly heritable risk factors for cardiovascular disease, with a complex genetic architecture.[3] Genome-wide association studies have pinpointed numerous genetic loci that modulate HDL cholesterol levels, encompassing genes such as ABCA1, APOA1-APOC3-APOA4-APOA5, CETP, LIPC, LIPG, and LPL, as well as identifying novel associations like a locus at 1q42 in an intron of GALNT2 where specific minor alleles can decrease HDL cholesterol concentrations. [3]These genetic insights are vital for deciphering the molecular mechanisms underlying HDL metabolism and its link to major comorbidities, particularly atherosclerosis, the foundational pathology for coronary artery disease and stroke.[2]The identification of specific single nucleotide polymorphisms, such as those withinCETP (rs289714 ), LIPC (rs2070895 ), and the APOA1-APOC3-APOA4-APOA5 cluster (rs10892044 ), illustrates the polygenic nature of dyslipidemia and its profound impact on cardiovascular health.[3]
References
Section titled “References”[1] Aulchenko YS, et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 1, 2008, pp. 143-50.
[2] Willer CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 1, 2008, pp. 161-9.
[3] Kathiresan S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, PMID: 19060906.
[4] Jiang XC 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. Clin. Invest. 1996; 98:2373–2380.
[5] Sabatti, C. et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, 2008.
[6] Gieger, Christian, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genetics, vol. 4, no. 11, Nov. 2008, p. e1000282.
[7] Ober, C, et al. “Genome-Wide Association Study of Plasma Lipoprotein(a) Levels Identifies Multiple Genes on Chromosome 6q.”J Lipid Res, vol. 50, no. 3, 2009, pp. 575-84.
[8] Spirin, V., et al. “Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol.”Am. J. Hum. Genet., vol. 81, 2007, pp. 1298–1303.
[9] Plump, Alice S., et al. “Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.”The Journal of Clinical Investigation, vol. 98, no. 11, 1996, pp. 2373-2380.
[10] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.
[11] Jiang XC et al. “Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.”J. Clin. Invest. 1999; 103:907–914.
[12] Isaacs A et al. “The - 514C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.” J. Clin. Endocrinol. Metab. 2004; 89:3858–3863.
[13] Phillipson BE et al. “Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia.” N. Engl. J. Med. 1985; 312:1210–1216.