Triglycerides In Small Hdl
Introduction
Section titled “Introduction”Triglycerides are a type of fat (lipid) found in the blood. They are the main form of fat stored in the body and are used for energy. High-density lipoprotein (HDL) is often referred to as “good cholesterol” because it helps remove excess cholesterol from the body and transport it back to the liver for excretion, a process known as reverse cholesterol transport. However, HDL exists in various sizes and compositions, ranging from larger, buoyant particles to smaller, denser ones. The presence of triglycerides within these HDL particles, particularly in smaller, denser subclasses, is a key area of study in lipid metabolism and cardiovascular health.
Biological Basis
Section titled “Biological Basis”The metabolism of triglycerides and HDL is intricately linked. In certain metabolic states, such as insulin resistance or hypertriglyceridemia, HDL particles can become enriched with triglycerides through the action of cholesteryl ester transfer protein (CETP), which exchanges cholesteryl esters in HDL for triglycerides from triglyceride-rich lipoproteins (such as VLDL). These triglyceride-enriched HDL particles are then more susceptible to hydrolysis by hepatic lipase, leading to the formation of smaller, denser, and often less functional HDL particles. These smaller HDL particles may have reduced capacity for reverse cholesterol transport and can even become pro-atherogenic, contributing to the development of plaque in arteries.
Clinical Relevance
Section titled “Clinical Relevance”Abnormal lipid profiles, including altered levels of triglycerides and HDL, are well-established risk factors for cardiovascular disease (CVD).[1]Specifically, an increase in triglycerides within small HDL particles is often associated with a higher risk of heart disease, even when total HDL cholesterol levels appear normal. This is because the functionality of HDL, rather than just its concentration, is crucial for its protective effects. Small, triglyceride-rich HDL may indicate a dysregulated lipid metabolism, which is a hallmark of conditions like metabolic syndrome and type 2 diabetes. Studies have shown an association between nonfasting triglycerides and an increased risk of cardiovascular events.[2]
Social Importance
Section titled “Social Importance”Understanding the role of triglycerides in small HDL particles is important for public health because it helps identify individuals at increased risk for cardiovascular disease who might otherwise be overlooked based on standard lipid panels. This detailed insight into lipoprotein subclasses allows for more targeted risk assessment and personalized interventions. Lifestyle modifications, such as diet and exercise, as well as certain medications, can impact the composition and functionality of HDL, potentially reducing the burden of cardiovascular disease in the population. The heritability of circulating lipid levels, including HDL and triglycerides, is well-established[1] suggesting a genetic component that, when understood, can further inform preventative and therapeutic strategies.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”While large-scale meta-analyses, combining data from tens of thousands of individuals, have significantly enhanced statistical power for identifying genetic associations [1], [3]individual discovery or constituent cohorts within these analyses may have possessed smaller sample sizes. This could potentially limit the detection of rarer genetic variants or those with more subtle effects on triglyceride levels. Furthermore, some contributing studies included individuals ascertained for specific diseases, such as diabetes, rather than being purely population-based[1]which may introduce ascertainment bias and affect the generalizability of effect size estimates to the broader healthy population. The necessary exclusion of individuals undergoing lipid-lowering therapy[3] means that the findings may not directly reflect genetic influences in treated individuals.
The assumption of an additive genetic model in many association analyses simplifies the complex underlying genetic architectures of traits like triglyceride levels[1], [3]potentially not fully capturing non-additive effects or gene-gene interactions. Although extensive replication efforts across independent cohorts were conducted to validate discovered loci [3], [4]the consistency of all identified associations across diverse replication strategies, and the potential for residual effect-size inflation for some less robust signals, remain important considerations. Minor variations in covariate adjustments, such as the exclusion ofage^2 in one cohort [3] and differing approaches to account for relatedness among participants in various studies [3] could also introduce subtle heterogeneities in the combined meta-analyses.
Generalizability and Phenotype Measurement Challenges
Section titled “Generalizability and Phenotype Measurement Challenges”A significant limitation in current research is the predominant focus on populations of European ancestry for discovery and many replication cohorts [1], [3]. [3] While some efforts were made to extend findings to multiethnic samples [3]results derived primarily from European populations may not fully generalize to other ancestral groups. This is due to potential differences in allele frequencies, patterns of linkage disequilibrium, and the underlying genetic architecture of triglyceride regulation across diverse populations, highlighting the critical need for more inclusive global studies.
Variability in the collection and processing of triglyceride levels can introduce noise and heterogeneity across studies. Although most studies emphasized the use of fasting blood samples[3] some cohorts allowed for shorter or more variable fasting durations [3]which can directly influence measured triglyceride concentrations. Furthermore, in certain cohorts, data on lipid-lowering therapy was unavailable and therefore not considered[3] potentially leading to the inclusion of individuals on treatment and obscuring true genetic effects. Differences in statistical methods for outlier exclusion and lipid transformation across cohorts further complicate a uniform and direct interpretation of findings. [3]
Incomplete Understanding of Genetic Architecture and Environmental Factors
Section titled “Incomplete Understanding of Genetic Architecture and Environmental Factors”Despite the identification of numerous genetic loci significantly associated with triglyceride levels, these common variants collectively explain only a small fraction of the trait’s overall heritability[3]. [1] For triglycerides, the explained variance was approximately 7.4% [3]indicating a substantial “missing heritability.” This suggests that a large proportion of genetic influences on triglyceride levels remains undiscovered, likely involving rarer variants, structural variations, or more complex genetic interactions not yet fully captured by current genome-wide association study methodologies. Further research with larger samples and improved statistical power is needed to uncover these additional genetic contributors.[3]
The current research predominantly focuses on identifying genetic associations while adjusting for fundamental demographic factors such as age, sex, and diabetes status [3]. [3]However, the comprehensive influence of specific environmental factors, including detailed dietary patterns, physical activity levels, or other physiological states, along with their interactions with genetic predispositions (gene-environment interactions), has not been extensively explored. The observation of sex-specific effects for certain loci[1]underscores the potential for complex biological mechanisms and environmental modifiers that require further elucidation for a complete understanding of triglyceride regulation and its clinical implications.
Variants
Section titled “Variants”Genetic variations across several key genes play a significant role in determining an individual’s lipid profile, particularly impacting triglyceride levels and the composition of small high-density lipoprotein (HDL) particles. These variants influence enzymes and regulatory proteins essential for the synthesis, breakdown, and transport of fats in the bloodstream, contributing to the overall metabolic balance.
Several variants are associated with the regulation of triglyceride catabolism and synthesis. Variants within the_LPL_ gene, such as *rs115849089 *, *rs328 *, and *rs144503444 *, affect Lipoprotein Lipase, an enzyme critical for breaking down triglycerides from lipoproteins in the bloodstream, allowing tissues to absorb fatty acids. Altered_LPL_activity can lead to changes in circulating triglyceride levels, directly influencing the triglyceride content and size of HDL particles.[4] Similarly, the _MLXIPL_gene, encoding a transcription factor that activates genes involved in fatty acid and triglyceride synthesis, is influenced by variants like*rs34060476 * and *rs13240994 *. These variations can modulate the body’s triglyceride production[4]affecting very-low-density lipoprotein (VLDL) production and the subsequent exchange of triglycerides with HDL. The_GCKR_ gene, specifically *rs1260326 *, influences the Glucokinase Regulatory Protein, which impacts glucose and lipid metabolism. The T allele of*rs1260326 *is associated with increased triglyceride concentrations[4]indicating its role in directing metabolic pathways towards triglyceride accumulation, thus affecting the triglyceride load of small HDL. The variant*rs964184 *, linked to _ZPR1_, is located near the APOA5-APOA4-APOC3-APOA1gene cluster, a region profoundly involved in triglyceride metabolism and HDL regulation. This SNP is associated with significant increases in triglyceride concentrations[4]highlighting its potential impact on lipoprotein composition, including small HDL.
Other genes and their variants are critical for HDL remodeling and cholesterol transport. The _CETP_ gene, with variants like *rs183130 * and *rs821840 *, encodes Cholesteryl Ester Transfer Protein, which mediates the exchange of cholesteryl esters from HDL to triglyceride-rich lipoproteins, and vice versa for triglycerides. Variations in_CETP_alter this exchange activity, affecting HDL cholesterol levels and the triglyceride enrichment of HDL[4] which is a major determinant of small HDL functionality. _LIPC_, or Hepatic Lipase, is another enzyme crucial for HDL metabolism, breaking down triglycerides and phospholipids within HDL particles, facilitating their maturation into smaller forms. The *rs1800588 * variant in _LIPC_can influence this enzymatic activity, impacting HDL cholesterol concentrations and the triglyceride content of HDL[4] which is particularly relevant for the metabolism of small HDL. Furthermore, the _APOE_-APOC1 gene cluster, including variants *rs1065853 * and *rs438811 *, plays a central role in the metabolism of various lipoproteins. _APOE_facilitates the clearance of triglyceride-rich lipoproteins, while_APOC1_ can modulate _CETP_ activity. Variations within this cluster affect overall lipid levels, including LDL and potentially HDL cholesterol [4]thereby indirectly influencing the triglyceride load and composition of small HDL particles.
The _TRIB1_ gene, and its variants *rs28601761 * and *rs2954021 *, also exert broad effects on lipid profiles. _TRIB1_ (Tribbles Homolog 1) is involved in various cellular processes, including the regulation of protein degradation pathways that control key enzymes and transcription factors vital for lipid synthesis and catabolism. Variations in _TRIB1_are associated with triglyceride levels and can also affect HDL cholesterol concentrations[4]indicating its pleiotropic influence on lipoprotein metabolism. These effects ultimately impact the overall metabolic environment, including the dynamic exchange of triglycerides in small HDL particles.
Key Variants
Section titled “Key Variants”Causes of Triglycerides in Small HDL
Section titled “Causes of Triglycerides in Small HDL”Genetic Predisposition and Regulation of Triglyceride Metabolism
Section titled “Genetic Predisposition and Regulation of Triglyceride Metabolism”The levels of triglycerides, including those found within small high-density lipoprotein (HDL) particles, are significantly influenced by an individual’s genetic makeup. Numerous common genetic variants across at least 30 distinct loci collectively contribute to a polygenic risk for dyslipidemia, a condition characterized by abnormal lipid levels.[3] Specifically, inherited variants in genes such as APOC3play a crucial role in regulating triglyceride metabolism. For instance, individuals carrying a null mutation (R19X) in theAPOC3gene exhibit substantially lower fasting and postprandial serum triglyceride levels, alongside higher HDL-cholesterol levels.[5]
Another significant genetic factor is the P446L allele (rs1260326 ) in the GCKR gene, which has been associated with increased concentrations of APOC3. [3] Since APOC3is a known inhibitor of triglyceride catabolism, higher levels ofAPOC3 due to this GCKR variant lead to a reduced clearance of triglycerides from the bloodstream. [3] Conversely, a reduction in functional APOC3, as seen with the null mutation, enhances triglyceride breakdown and clearance, resulting in a more favorable lipid profile.[5]
Interplay of Genetic Factors and Lipid Dynamics
Section titled “Interplay of Genetic Factors and Lipid Dynamics”Genetic variations profoundly influence the dynamic processes of lipid metabolism, directly impacting the circulating levels of triglycerides. The APOC3protein, primarily synthesized in the liver, acts as a key inhibitor of triglyceride catabolism, interfering with the enzymatic breakdown and clearance of triglyceride-rich lipoproteins.[3] Therefore, inherited predispositions that increase APOC3 expression, such as the GCKR P446L allele, can lead to chronic elevations in plasma triglycerides by hindering their efficient removal. [3]
Conversely, genetic variations that reduce or eliminate APOC3function, like the R19X null mutation, accelerate triglyceride clearance, leading to lower circulating triglyceride concentrations and an improvement in overall lipid parameters, including HDL-cholesterol levels.[5]Elevated triglyceride levels, particularly non-fasting triglycerides, are associated with the generation of atherogenic remnant lipoproteins during the digestion and clearance of dietary fat, which are implicated in cardiovascular disease risk.[5]This highlights how genetic variants affecting triglyceride metabolism can alter the spectrum of circulating lipoproteins and their atherogenicity.
Lifestyle Influences and Systemic Health Implications
Section titled “Lifestyle Influences and Systemic Health Implications”Lifestyle choices and dietary patterns significantly interact with genetic predispositions to influence triglyceride levels. The consumption of dietary fat, for instance, directly impacts postprandial triglyceride responses, with genetic factors playing a role in how individuals metabolize and clear these fats.[5] While genetic variants like those in APOC3can offer substantial protection against high triglycerides, environmental factors, including diet, can modulate the expression of triglyceride-related traits.
Beyond direct dietary influences, elevated plasma triglycerides, along with high LDL-cholesterol, are well-established risk factors for the development of premature coronary heart disease.[5]Non-fasting triglyceride levels have been shown to be an independent predictor of coronary heart disease, sometimes demonstrating higher predictive power than traditional fasting triglyceride measures, likely due to their association with atherogenic remnant lipoproteins.[5]Thus, managing lifestyle factors becomes crucial, especially for individuals with genetic susceptibilities, to mitigate the cardiovascular risks associated with high triglycerides.
Biological Background
Section titled “Biological Background”Lipoprotein Metabolism and Triglyceride Dynamics
Section titled “Lipoprotein Metabolism and Triglyceride Dynamics”Triglycerides are fundamental lipid molecules that serve as a primary energy storage form and are crucial for lipid transport throughout the body. These lipids are transported within the bloodstream packaged into various lipoprotein particles, including very-low-density lipoproteins (VLDL) and chylomicrons. Following a high-fat meal, the body experiences a postprandial lipemic response, characterized by an increase in plasma triglyceride levels as these lipoproteins are digested and absorbed.[6]This dynamic process involves a coordinated effort of synthesis, secretion, and catabolism of triglyceride-rich lipoproteins by organs such as the liver and intestine.
High-density lipoprotein (HDL) plays a vital role in reverse cholesterol transport, but its composition, particularly its triglyceride content, is subject to continuous remodeling in plasma. Small HDL particles are particularly prone to changes in their triglyceride levels, which can significantly influence their structure and function. The overall lipid environment, influenced by diet and metabolic processes, dictates the balance of these circulating lipoproteins and the specific lipid load carried by different HDL subspecies.
Key Enzymes and Protein Interactions in HDL Remodeling
Section titled “Key Enzymes and Protein Interactions in HDL Remodeling”The intricate remodeling of HDL particles, which dictates their size and lipid composition, is governed by several crucial enzymes and proteins. Among these,Phospholipid Transfer Protein (PLTP) is a key biomolecule that facilitates the transfer of phospholipids and, to a lesser extent, triglycerides between various lipoproteins. This protein’s activity is essential for the maturation and remodeling of HDL, impacting its overall levels in the circulation.[7] Research indicates that targeted genetic modifications, such as the mutation of the PLTP gene, can lead to a marked reduction in plasma HDL levels, highlighting its critical role in maintaining HDL homeostasis. [7]
Another significant enzyme involved in lipid metabolism and HDL remodeling is Hepatic Lipase, encoded by the LIPCgene. This enzyme catalyzes the hydrolysis of phospholipids and triglycerides within various lipoprotein particles, thus influencing their size and composition. Genetic variations, such as the -514C->T polymorphism in the promoter region of theLIPC gene, have been linked to altered plasma lipid levels, underscoring the genetic regulatory mechanisms that control this enzyme’s activity and, consequently, its impact on lipid profiles. [8]The orchestrated actions of these enzymes are crucial for the proper exchange and processing of lipids, directly affecting the triglyceride content of small high-density lipoprotein.
Genetic and Environmental Determinants of Dyslipidemia
Section titled “Genetic and Environmental Determinants of Dyslipidemia”Dyslipidemia, a condition characterized by abnormal lipid levels including triglycerides, is largely considered to have a polygenic basis, meaning that a multitude of genetic variants collectively contribute to its manifestation. [3] The complex genetic architecture underlying hypertriglyceridemia, a key component of dyslipidemia, involves many genes and regulatory elements that impact lipid metabolism. [9]These common genetic variants found across numerous genomic loci influence the intricate regulatory networks governing the function of enzymes, receptors, and other proteins critical for lipoprotein metabolism, thereby modulating the concentration of triglycerides within various lipoprotein subclasses, including small high-density lipoprotein.[3]
Beyond genetic predispositions, environmental factors, particularly dietary habits, play a substantial role in shaping an individual’s lipid profile and the triglyceride content of lipoproteins. For instance, controlled dietary interventions involving fish oils have demonstrated a notable ability to reduce plasma lipids, lipoproteins, and apoproteins in patients presenting with hypertriglyceridemia.[10]This highlights the dynamic interplay between an individual’s inherited genetic blueprint and external environmental stimuli, both of which are critical determinants of systemic lipid homeostasis and the specific characteristics of circulating high-density lipoprotein particles.
Pathophysiological Implications of Altered Triglycerides in Small High-Density Lipoprotein
Section titled “Pathophysiological Implications of Altered Triglycerides in Small High-Density Lipoprotein”Dysregulation of triglyceride levels, especially within small high-density lipoprotein particles, is intimately associated with pathophysiological processes linked to an elevated risk of cardiovascular diseases. Elevated plasma triglyceride levels, particularly those observed in the postprandial period, are indicative of impaired lipid clearance mechanisms and are a recognized factor contributing to the development and progression of metabolic syndrome and coronary artery disease.[6] This disruption in normal homeostatic lipid processing reflects an imbalance between the body’s capacity to synthesize and catabolize circulating lipoproteins.
The systemic consequences of altered lipid profiles extend broadly, impacting various tissues and organs, including the endothelium, and contributing to the initiation and progression of atherosclerosis. The remodeling processes that yield smaller, denser high-density lipoprotein particles, which are often enriched with triglycerides, are thought to diminish the protective, anti-atherogenic functions typically attributed to high-density lipoprotein. Consequently, a comprehensive understanding of the molecular and cellular factors that regulate triglyceride levels within small high-density lipoprotein is paramount for elucidating its role in cardiovascular pathology.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”HDL Biogenesis and Remodeling Factors
Section titled “HDL Biogenesis and Remodeling Factors”The formation and subsequent remodeling of high-density lipoprotein (HDL) particles are complex metabolic processes critical for lipid transport, with specific proteins orchestrating their composition and size. Early-stage HDL, known as prebeta-HDL, is characterized by its nascent structure, primarily composed ofApolipoprotein AI (ApoAI) and phospholipids. [7] ApoAI serves as a foundational component, facilitating cholesterol efflux and providing structural integrity to the evolving HDL particle. The Phospholipid Transfer Protein (PLTP) plays a crucial role in these dynamic changes by transferring phospholipids between lipoproteins, directly influencing HDL particle size and lipid content. Mice expressing humanPLTP and ApoAI transgenes exhibit increased levels of prebeta-HDL, ApoAI, and phospholipids, demonstrating the intricate relationship between these components in promoting HDL biogenesis and remodeling. [7] Furthermore, targeted mutation of the PLTPgene in plasma markedly reduces overall high-density lipoprotein levels, highlighting its indispensable function in maintaining a healthy HDL pool and suggesting a significant impact on the ultimate triglyceride content within small HDL particles.[11]
Enzymatic Hydrolysis and Genetic Modifiers of HDL Lipids
Section titled “Enzymatic Hydrolysis and Genetic Modifiers of HDL Lipids”The enzymatic hydrolysis of triglycerides and phospholipids within circulating lipoproteins is a key metabolic pathway that significantly influences the composition and size of HDL, including its triglyceride content. Hepatic Lipase (HL), encoded by the LIPCgene, is a crucial enzyme that hydrolyzes these lipids, thereby promoting the conversion of larger, triglyceride-rich HDL into smaller, denser particles . This process directly impacts the half-life and function of HDL particles, affecting their capacity to participate in reverse cholesterol transport. Genetic variations, such as the -514C->T polymorphism in theHL promoter region, can modulate HLexpression and activity, subsequently altering plasma lipid profiles and contributing to changes in HDL subfraction distribution and triglyceride loading . Such regulatory mechanisms at the gene level exert allosteric control over lipid metabolism, influencing the overall flux of triglycerides within the HDL spectrum.
Systemic Lipid Homeostasis and Therapeutic Modulation
Section titled “Systemic Lipid Homeostasis and Therapeutic Modulation”The systemic regulation of lipid metabolism involves complex interactions across various pathways, where dysregulation can lead to conditions like hypertriglyceridemia and altered lipoprotein profiles, including increased triglycerides in small HDL. Dietary interventions represent a significant strategy to modulate these metabolic pathways and restore lipid homeostasis. For instance, dietary fish oils, rich in omega-3 fatty acids, are known to reduce plasma lipids, lipoproteins, and apoproteins in patients with hypertriglyceridemia.[10]This therapeutic effect likely involves a cascade of metabolic regulations, influencing biosynthesis and catabolism pathways of triglycerides and very-low-density lipoproteins (VLDL), thereby indirectly impacting the triglyceride load and size of HDL particles. The observed reduction in plasma lipids underscores a systems-level integration where dietary factors can trigger broad metabolic adjustments, offering a compensatory mechanism against dyslipidemia.
Polygenic Influences on Lipoprotein Phenotypes
Section titled “Polygenic Influences on Lipoprotein Phenotypes”Lipoprotein phenotypes, including the concentration of triglycerides in small HDL, are often the result of complex interactions between multiple genetic loci and environmental factors, collectively contributing to polygenic dyslipidemia.[1] Common variants across numerous genes, such as those encoding PLTP and Hepatic Lipase (LIPC), can individually exert subtle effects on lipid metabolism, which, when combined, contribute to the emergent properties of an individual’s lipid profile. [1]Pathway crosstalk among enzymes involved in HDL remodeling, triglyceride hydrolysis, and lipid transfer dictates the precise composition and size distribution of HDL particles. Understanding this hierarchical regulation and network interactions is crucial for elucidating the underlying mechanisms of lipoprotein dysregulation and identifying potential therapeutic targets for managing conditions characterized by abnormal triglyceride levels in small HDL.
Clinical Relevance
Section titled “Clinical Relevance”Prognostic Value and Cardiovascular Disease Risk
Section titled “Prognostic Value and Cardiovascular Disease Risk”Elevated triglyceride levels, even in the non-fasting state, are associated with an increased risk of cardiovascular events, indicating their significant prognostic value in assessing patient outcomes.[2]Genetic studies have identified specific loci influencing triglyceride levels that also correlate with cardiovascular disease risk. For instance, alleles associated with increased triglyceride concentrations near theTRIB1 gene, such as at rs17321515 , have been directly linked to an elevated risk of coronary artery disease.[4]This suggests that genetic predispositions to higher triglycerides can independently predict future cardiovascular complications and disease progression, offering insights into long-term health implications beyond traditional lipid measurements.
Furthermore, integrating genetic risk profiles with established clinical risk factors, such as lipid values, age, and body mass index, can enhance the prediction of coronary heart disease.[1]While individual genetic variants may have small effect sizes, their cumulative impact can be substantial. For example, a genetic risk score for total cholesterol, which is a composite ofLDL, HDL, and VLDLcholesterol, has shown significant association with clinically defined hypercholesterolemia and increased intima-media thickness, a marker of atherosclerosis.[1]This improved risk classification highlights the utility of genetic information in refining prognostic assessments for individuals at risk of cardiovascular conditions.
Clinical Applications in Risk Assessment and Personalized Prevention
Section titled “Clinical Applications in Risk Assessment and Personalized Prevention”The identification of genetic loci influencing triglyceride andHDLcholesterol levels offers critical applications in clinical practice, particularly for refined risk assessment and personalized medicine. Genetic risk scores, developed from multiple associated single nucleotide polymorphisms, allow for the identification of individuals at higher genetic risk for dyslipidemia and related complications.[1] For instance, the TC genetic risk score improved the prediction of hypercholesterolemia beyond traditional factors like age, sex, and BMI. [1]Such scores can guide prevention strategies, potentially enabling earlier intervention through lifestyle modifications or pharmacotherapy in genetically predisposed high-risk groups.
Monitoring strategies can also benefit from these genetic insights. While screening for elevated circulating lipid levels and initiating early treatment with statins are standard preventive measures, understanding an individual’s genetic landscape can inform more targeted approaches. [1] For example, variations in genes like HMGCR have been associated with differential responses to statin treatment, suggesting a future where pharmacogenomic testing could optimize treatment selection for lipid-lowering therapies. [12] This move towards personalized medicine could enhance the effectiveness of interventions and improve patient outcomes by tailoring therapeutic choices to individual genetic profiles.
Comorbidities, Overlapping Phenotypes, and Metabolic Associations
Section titled “Comorbidities, Overlapping Phenotypes, and Metabolic Associations”Triglyceride andHDL cholesterol levels are intricately linked with broader metabolic health and various comorbidities. Genetic studies reveal associations between lipid-influencing loci and pathways involved in cholesterol and sterol metabolism, lipid transport, and nutrient response, underscoring the systemic nature of dyslipidemia. [1] The observed positive correlation between increased LDLcholesterol and triglyceride concentrations, sometimes driven by shared genetic influences such as a SNP nearCILP2 (rs16996148 ), illustrates the overlapping phenotypes in dyslipidemia. [4] This highlights that interventions targeting one lipid component may have broader effects across the lipid profile.
Moreover, genetic effects on lipid levels can exhibit sex-specific differences, as seen with HMGCR (rs3846662 ) and NCANinfluencing total cholesterol, andLPL (rs2083637 ) affecting HDL cholesterol, which further complicates the syndromic presentations of dyslipidemia. [1]These findings suggest that genetic susceptibility to dyslipidemia contributes to a complex interplay of metabolic traits, influencing conditions such as obesity (e.g.,FTO gene association with body mass) [2] and fatty acid metabolism (FADS1-FADS2 locus). [13] Recognizing these interconnected genetic and phenotypic associations is crucial for a holistic understanding and management of patients with complex metabolic disorders.
References
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[2] Wallace, C. et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139–149. PMID: 18179892.
[3] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.
[4] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161–169. PMID: 18193043.
[5] Pollin, T.I. et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, no. 5906, 2008, pp. 1702-1705.
[6] Alcala-Diaz, JF, et al. “Hypertriglyceridemia influences the degree of postprandial lipemic response in patients with metabolic syndrome and coronary artery disease: from the CORDIOPREV study.”PloS one, vol. 9, no. 5, 2014, p. e96297.
[7] 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., vol. 98, 1996, pp. 2373–2380.
[8] Isaacs, A, et al. “The -514C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.” J. Clin. Endocrinol. Metab., vol. 89, 2004, pp. 3858–3863.
[9] Hegele, RA, et al. “The polygenic nature of hypertriglyceridaemia.” Metabolism, 2016.
[10] Phillipson, BE, et al. “Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia.” N. Engl. J. Med., vol. 312, 1985, pp. 1210–1216.
[11] Jiang, XC, et al. “Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.”J. Clin. Invest., vol. 103, 1999, pp. 907-914.
[12] Burkhardt, R. et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, vol. 28, no. 10, 2008, pp. 1827–1834. PMID: 18802019.
[13] Sabatti, C. et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 40, no. 12, 2008, pp. 1426–1432. PMID: 19060910.