Triglycerides In Hdl
High-density lipoprotein (HDL) is a class of lipoproteins traditionally known for its role in transporting cholesterol from peripheral tissues back to the liver, a process termed reverse cholesterol transport. Often referred to as “good cholesterol,” HDL particles are complex and dynamic, carrying various lipids, including triglycerides. Triglycerides are the main form of fat stored in the body and are a primary source of energy. While HDL is primarily associated with cholesterol, the amount of triglycerides carried within HDL particles, and the overall composition of these particles, is an important aspect of lipid metabolism with significant biological and clinical implications.
Biological Basis
Section titled “Biological Basis”HDL particles are heterogeneous, existing in various sizes and densities, often categorized into subfractions like HDL2 and HDL3. [1]The triglyceride content within HDL particles is influenced by the exchange of lipids with other lipoproteins, particularly very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), a process mediated by enzymes such as cholesteryl ester transfer protein (CETP) and hepatic lipase (HL). When triglyceride-rich lipoproteins are abundant, such as after a meal or in states of insulin resistance, CETP facilitates the exchange of triglycerides from VLDL/LDL into HDL particles in return for cholesteryl esters. This enrichment of HDL with triglycerides makes them a substrate for hepatic lipase, which hydrolyzes these triglycerides, leading to smaller, more dense, and often dysfunctional HDL particles that are more rapidly catabolized. Genetic factors play a role in regulating triglyceride metabolism; for instance, theGCKR P446L allele (rs1260326 ) has been associated with increased concentrations of APOC-III, an inhibitor of triglyceride catabolism synthesized in the liver.[1] Higher APOC-IIIlevels can lead to reduced triglyceride breakdown, potentially impacting the triglyceride content of HDL and other lipoproteins.
Clinical Relevance
Section titled “Clinical Relevance”The concentration of triglycerides in HDL, often assessed indirectly through the ratio of triglycerides to HDL-cholesterol, is gaining recognition as a marker of cardiovascular risk. While high HDL-cholesterol levels are generally considered protective against atherosclerotic cardiovascular disease, HDL particles that are rich in triglycerides and subsequently smaller and denser may be less effective in their protective functions, such as reverse cholesterol transport and anti-inflammatory activities. High triglycerides in HDL are frequently observed in conditions like metabolic syndrome, insulin resistance, and type 2 diabetes. Therefore, understanding the triglyceride content within HDL can provide a more nuanced picture of an individual’s lipid profile and cardiovascular risk beyond standard total HDL-cholesterol measurements.
Social Importance
Section titled “Social Importance”The societal impact of understanding triglycerides in HDL relates to public health strategies for preventing and managing cardiometabolic diseases. As cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, detailed insights into lipid metabolism, including the composition of HDL particles, can inform more precise risk stratification and personalized treatment approaches. Promoting healthy lifestyles, including diet and exercise, which can influence both overall triglyceride levels and the composition of HDL, forms a cornerstone of public health efforts. Research into genetic predispositions, such as variants affectingAPOC-IIIand triglyceride catabolism[1]contributes to the growing field of precision medicine, allowing for more targeted interventions to improve lipid profiles and reduce disease burden in at-risk populations.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”While the genetic studies of triglyceride and HDL cholesterol levels leverage large cohorts and meta-analysis techniques to enhance statistical power, certain methodological and statistical constraints limit the comprehensiveness of their findings. The reliance on genome-wide association studies (GWAS) often favors the detection of common variants with modest effect sizes, potentially overlooking rarer variants or those with more complex inheritance patterns that also contribute to lipid regulation.[1] Furthermore, the consistent application of an additive genetic model simplifies the underlying biological reality, as it may not fully capture potential gene-gene interactions (epistasis) or non-additive effects that could influence lipid phenotypes. [1]
Minor variations in analytical approaches and data preprocessing across different cohorts within meta-analyses could also introduce subtle biases. For instance, some studies excluded specific covariates like age2 or lacked complete information on lipid-lowering therapy, leading to inconsistent adjustments across the pooled data. [1] Such differences, alongside the use of adjusted residuals as phenotypes, mean that reported associations are with these statistically derived values rather than directly measured lipid concentrations, which might slightly complicate direct clinical interpretation of effect sizes. Although genomic control correction was applied to mitigate population stratification, residual confounding could still exist. [2]
Generalizability and Phenotypic Heterogeneity
Section titled “Generalizability and Phenotypic Heterogeneity”A significant limitation is the predominant ascertainment of study participants from populations of European ancestry. [1] While efforts were made to include multiethnic cohorts in some replication stages, the generalizability of identified genetic loci and their estimated effect sizes to other ancestral groups remains largely unconfirmed. Genetic architecture, including allele frequencies and linkage disequilibrium patterns, can vary substantially across different populations, meaning that findings from one group may not be directly transferable or possess the same predictive value in another. [3] This lack of diverse representation limits the global applicability of the genetic insights obtained and underscores the need for broader ethnic inclusion in future research.
Furthermore, despite standardization attempts, phenotypic ascertainment exhibited some inconsistencies across studies. Variations in fasting protocols, such as required fasting times, were noted, which could impact triglyceride levels in particular.[1] Similarly, the exclusion of individuals on lipid-lowering therapy was not uniformly applied or recorded across all cohorts, potentially leading to residual confounding in some analyses and influencing the observed genetic associations. [1] These differences in phenotype definition and measurement fidelity across the combined cohorts could introduce heterogeneity and slightly attenuate the power to detect true associations or accurately estimate their impact.
Unexplained Variation and Complex Interactions
Section titled “Unexplained Variation and Complex Interactions”Despite the identification of numerous genetic loci associated with triglyceride and HDL cholesterol levels, these common variants collectively explain only a modest fraction of the total phenotypic variability observed in the population.[2] This “missing heritability” suggests that a substantial portion of the genetic influences on lipid metabolism remains unexplained, likely due to the contributions of rare variants, structural genetic variations, and complex gene-gene or gene-environment interactions that are not fully captured by current GWAS methodologies. The limited explanatory power of common variants highlights the need for advanced sequencing technologies and analytical approaches to uncover these elusive genetic factors.
Beyond genetic factors, the influence of unmeasured environmental and lifestyle confounders represents a critical knowledge gap. While studies adjusted for basic demographic and clinical variables like age, sex, and diabetes status[1]comprehensive data on dietary habits, physical activity levels, and other lifestyle factors that profoundly impact lipid profiles were largely unaccounted for. These environmental elements, and their intricate interplay with genetic predispositions, can significantly modulate an individual’s lipid levels and the expression of genetic risk, making it challenging to fully delineate the etiology of dyslipidemia. Moreover, some studies noted sex-specific differences in the effects of certain loci on lipid levels[2] indicating that sexually dimorphic biological mechanisms warrant further in-depth investigation.
Variants
Section titled “Variants”Genetic variations play a crucial role in determining an individual’s lipid profile, influencing the circulating levels of triglycerides and high-density lipoprotein (HDL) cholesterol. These variants impact genes involved in lipid synthesis, transport, and catabolism, thereby affecting the overall balance of lipoproteins and their components, including the triglyceride content within HDL particles. Many of these genetic loci have been consistently identified through genome-wide association studies (GWAS) as significant determinants of lipid concentrations, providing insights into the complex interplay of metabolic pathways.
Several genes are central to the synthesis and breakdown of triglycerides and the regulation of HDL cholesterol. The APOEgene encodes apolipoprotein E, a key component of chylomicrons and very-low-density lipoproteins (VLDL), essential for their clearance from the bloodstream by binding to lipoprotein receptors. Variants in theAPOEregion are strongly associated with LDL cholesterol levels and contribute to the polygenic nature of dyslipidemia, affecting the metabolism of triglyceride-rich particles and subsequently HDL metabolism.[4] LPL, or lipoprotein lipase, is a critical enzyme that hydrolyzes triglycerides from VLDL and chylomicrons, making it fundamental for triglyceride clearance; variations likers12679834 can significantly impact circulating triglyceride levels and, consequently, HDL cholesterol concentrations.[4] Similarly, the LIPCgene encodes hepatic lipase, an enzyme primarily involved in HDL metabolism and the conversion of intermediate-density lipoproteins (IDL) to LDL. Its activity directly influences HDL particle size and composition, impacting the exchange of triglycerides and cholesterol esters between lipoproteins.[4]
Other genes exert their influence on lipid profiles by regulating triglyceride synthesis and metabolism. TheGCKRgene, encoding glucokinase regulatory protein, plays a role in glucose and lipid metabolism in the liver. Variants such asrs1260326 have a strong association with elevated triglyceride levels, where the minor allele can lead to an increase in triglyceride concentrations, often accompanied by changes in HDL cholesterol.[4] The MLXIPLgene, also known as ChREBP, encodes a transcription factor that activates genes involved in fatty acid and triglyceride synthesis in response to carbohydrate intake. Variations inMLXIPL, like rs34060476 , are significantly associated with increased plasma triglyceride concentrations, reflecting enhanced hepatic lipid production.[4] Furthermore, the region near the APOA5 gene cluster, which includes the variant rs964184 , is a major determinant of triglyceride levels.APOA5is crucial for regulating triglyceride hydrolysis, influencing the activity of lipoprotein lipase and thereby profoundly affecting circulating triglyceride concentrations and the overall lipid environment, including the triglyceride content within HDL.[4]
Beyond direct lipid processing, some variants influence lipid metabolism through broader regulatory or signaling pathways. The DOCK7gene, involved in cell signaling, has been identified as a locus influencing serum triglyceride levels, suggesting a role in metabolic processes that can affect lipid partitioning and the composition of lipoproteins.[5] The TRIB1gene, encoding Tribbles homolog 1, is another significant locus consistently associated with triglyceride concentrations.TRIB1influences lipid metabolism by modulating the stability and degradation of key regulatory proteins, thereby impacting the synthesis and clearance of triglyceride-rich lipoproteins.[4] While ALDH1A2 (aldehyde dehydrogenase 1 family member A2), with variants such as rs1077835 , rs1601935 , and rs10162642 , is not explicitly detailed in the context for its direct lipid associations, it is involved in retinoic acid synthesis, which broadly impacts metabolic pathways including those related to lipid synthesis and catabolism, thus potentially influencing triglyceride levels and HDL composition.[4]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Triglycerides and High-Density Lipoprotein Cholesterol: Definitions and Physiological Significance
Section titled “Triglycerides and High-Density Lipoprotein Cholesterol: Definitions and Physiological Significance”Triglycerides are a type of fat found in the blood, serving as the primary form of energy storage in the body. High concentrations of triglycerides are a recognized risk factor for various health conditions, particularly cardiovascular disease. High-density lipoprotein (HDL) cholesterol, often referred to as “good cholesterol,” is a specific type of cholesterol carried by HDL particles that is inversely associated with cardiovascular risk.[4]While triglycerides are predominantly carried within very-low-density lipoprotein (VLDL) particles, the research provided treats triglycerides and HDL cholesterol as distinct, measurable biomarker traits crucial for assessing lipid metabolism. Both lipoprotein-associated lipid concentrations are consistently and compellingly linked to the incidence of cardiovascular disease globally.[4]Each 1% increase in HDL cholesterol concentrations is estimated to reduce the risk of coronary heart disease by approximately 2%, highlighting its protective role.[4]
Measurement and Operational Parameters of Lipid Traits
Section titled “Measurement and Operational Parameters of Lipid Traits”The precise measurement of lipid traits like triglycerides and HDL cholesterol is foundational for both clinical diagnostics and research. Concentrations of total cholesterol, HDL cholesterol, and triglycerides are typically determined from fasting blood samples using standard enzymatic methods.[1] Fasting periods often specify a minimum of 4 hours, with studies reporting mean fasting times around 6 ± 4 hours. [1]In genetic association studies, triglyceride levels are commonly natural log transformed before analysis to account for their typical skewed distribution.[6]Multivariable adjustments are applied to both HDL cholesterol and log-transformed triglyceride values to control for potential confounders such as age, age squared, gender, diabetes status, and the enrolling center of study participants.[1] Additionally, some studies incorporate ancestry-informative principal components into regression models to address population substructure within samples. [7] For analytical accuracy, individuals on lipid-lowering therapy, those who have not fasted, or those diagnosed with diabetes are generally excluded from lipid trait analyses. [6]
Clinical Classification and Associated Terminology of Dyslipidemia
Section titled “Clinical Classification and Associated Terminology of Dyslipidemia”Clinical guidelines establish specific thresholds for classifying lipid levels. According to National Cholesterol Education Program guidelines, a normal range for triglycerides is considered to be 30–149 mg/dl, while for HDL cholesterol, it ranges from 40–80 mg/dl. [8]Deviations from these normal ranges contribute to a condition known as dyslipidemia, which signifies abnormal lipid levels and is a key risk factor for cardiovascular disease.[7] The heritability of circulating lipid levels, including HDL and triglycerides, is well-established, indicating a significant genetic component to their variation within the population. [2]High triglyceride levels are also a defining component of the metabolic syndrome, a cluster of conditions that increase the risk of heart disease, stroke, and type 2 diabetes.[9] Research has identified numerous genetic loci influencing these lipid traits; for instance, ABCA1, CELSR2, CETP, LIPC, LIPG, CTCF-PRMT7, and MADD-FOLH1 are associated with HDL levels, while GCKR, LPL, APOA5-APOA4-APOC3-APOA1, DOCK7, MLXIPL, TRIB1, and specific variants near NCAN such as rs16996148 and rs2228603 are linked to triglyceride concentrations.[2]
Causes
Section titled “Causes”Genetic Predisposition and Lipid Homeostasis
Section titled “Genetic Predisposition and Lipid Homeostasis”Genetic factors significantly influence the intricate balance of lipid metabolism, thereby contributing to the presence of triglycerides in HDL particles. Dyslipidemia, characterized by abnormal lipid levels, often has a polygenic basis, meaning that variations across multiple genes collectively increase an individual’s susceptibility. Research indicates that common genetic variants at numerous loci contribute to this polygenic dyslipidemia, impacting various apolipoproteins and lipoprotein particle concentrations.[1]
One notable example is the GCKR P446L allele, specifically rs1260326 , which has been associated with elevated concentrations of APOC-III. [1] APOC-III, synthesized in the liver, is a critical inhibitor of triglyceride catabolism; therefore, its increased presence due to this genetic variant leads to reduced clearance of triglycerides from the bloodstream.[1]This systemic increase in triglycerides can result in their enhanced transfer into HDL particles, altering HDL composition and contributing to higher triglyceride content within HDL.
Biological Background
Section titled “Biological Background”Regulation of Lipid Metabolism and Triglyceride Homeostasis
Section titled “Regulation of Lipid Metabolism and Triglyceride Homeostasis”Lipid metabolism is a complex and highly regulated biological process essential for energy storage, cell membrane integrity, and hormone production. Critical to this regulation are various genes and their encoded proteins, which collectively maintain the balance of lipid concentrations in the blood, including triglycerides and high-density lipoprotein (HDL). For instance, the protein homolog ofANGPTL3 serves as a significant regulator of lipid metabolism, influencing systemic lipid levels. [4] Similarly, rare genetic variations in the related gene, ANGPTL4, have been directly linked to human HDL and triglyceride concentrations, underscoring the Angiopoietin-like protein family’s role in lipid homeostasis.[4] Furthermore, MLXIPLencodes a protein that actively binds to and stimulates specific regulatory sequences within the promoter regions of genes involved in triglyceride synthesis, thereby directly controlling the production of triglycerides.[4] These interconnected molecular and cellular pathways highlight the intricate network governing lipid availability and distribution throughout the body.
Genetic Determinants of Lipid Concentrations
Section titled “Genetic Determinants of Lipid Concentrations”Genetic mechanisms play a pivotal role in establishing an individual’s lipid profile, with specific genomic loci influencing circulating triglyceride levels and the risk of coronary artery disease. Single nucleotide polymorphisms (SNPs) located near the genesTRIB1, MLXIPL, and ANGPTL3have been identified as contributors to variations in triglyceride concentrations.[4] The coordinated expression of genes is also evident in the case of MVK and MMAB, which are neighboring genes regulated by the transcription factor SREBP2 and share a common promoter. [4] This shared regulatory control indicates a linked genetic mechanism influencing their respective metabolic functions. Moreover, the gene GALNT2 encodes a widely expressed glycosyltransferase, a class of enzymes that could potentially modify the structure of lipoproteins or their receptors, thereby impacting how these lipid-carrying particles are recognized and metabolized within the body. [4]
Cholesterol Biosynthesis and Degradation Pathways
Section titled “Cholesterol Biosynthesis and Degradation Pathways”Beyond general lipid regulation, specific pathways govern cholesterol metabolism, which is intrinsically linked to triglyceride and HDL levels.MVK encodes mevalonate kinase, a crucial enzyme that catalyzes an early and rate-limiting step in the extensive biochemical pathway of cholesterol biosynthesis. [4] This process is fundamental for producing cholesterol, a key component of cell membranes and a precursor for steroid hormones. Conversely, the gene MMAB encodes a protein that participates in a distinct metabolic pathway responsible for the degradation of cholesterol. [4] The balanced activity of these genes, MVK and MMAB, under the regulatory control of factors like SREBP2, is therefore essential for maintaining cholesterol homeostasis and preventing its accumulation or deficiency, which can have systemic consequences. [4]
Pathophysiological Implications for Cardiovascular Health
Section titled “Pathophysiological Implications for Cardiovascular Health”Disruptions in the precise regulation of lipid metabolism, including triglyceride and HDL concentrations, have significant pathophysiological consequences, particularly for cardiovascular health. The identification of genetic loci that influence lipid concentrations also suggests a heightened risk of developing coronary artery disease.[4]This connection underscores how imbalances in homeostatic processes—such as aberrant triglyceride synthesis driven by genes likeMLXIPL, or dysregulation of overall lipid metabolism by ANGPTL3 and ANGPTL4—can contribute to disease mechanisms.[4] The interplay between cholesterol synthesis (MVK) and degradation (MMAB) pathways, along with the potential modification of lipoproteins by enzymes like GALNT2, collectively illustrates how finely tuned molecular and cellular functions at the tissue and organ level impact systemic lipid profiles and, consequently, long-term cardiovascular well-being.[4]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”HDL Biogenesis and Remodeling
Section titled “HDL Biogenesis and Remodeling”Apolipoprotein AI (APOA1) is a core structural protein of HDL, essential for its formation and functionality. Phospholipid transfer protein (PLTP) plays a crucial role in the biogenesis and remodeling of HDL particles. A targeted mutation in the PLTPgene significantly reduces high-density lipoprotein levels, demonstrating its importance in maintaining adequate circulating HDL.[10] This mechanism underscores how PLTP’s activity impacts the structural integrity and abundance of HDL particles, which in turn influences their capacity to carry and exchange triglycerides.
Lipid Catabolism and Metabolic Regulation
Section titled “Lipid Catabolism and Metabolic Regulation”Hepatic lipase (LIPC) is an enzyme that plays a key role in the hydrolysis of triglycerides and phospholipids in various lipoproteins, including HDL. A polymorphism in the LIPC promoter region, specifically the rs-514C->T variant, has been linked to variations in plasma lipid profiles, indicating its role in metabolic regulation. [11] This genetic variation can influence LIPCexpression or activity, thereby altering the catabolic rate of HDL components and and the overall flux of lipids within the metabolic network. Such regulation is critical for maintaining healthy triglyceride levels within HDL and across the broader lipoprotein spectrum.
Dietary Modulation of Lipid Metabolism
Section titled “Dietary Modulation of Lipid Metabolism”Dietary factors are significant regulators of lipid metabolism, affecting plasma triglycerides, lipoproteins, and apoproteins. For instance, in individuals with hypertriglyceridemia, the consumption of dietary fish oils has been shown to reduce plasma levels of lipids, lipoproteins, and apoproteins. [12]This suggests that specific dietary components can modulate metabolic pathways involved in lipid synthesis, catabolism, or transfer, thereby influencing the overall lipid profile and potentially the triglyceride content within HDL particles. Such dietary interventions offer a systemic approach to regulate metabolic flux and manage dyslipidemia.
Genetic Architecture of Dyslipidemia
Section titled “Genetic Architecture of Dyslipidemia”Dyslipidemia, characterized by abnormal lipid levels including triglycerides, is often a complex trait influenced by multiple genetic factors. Research indicates that common genetic variants at numerous loci contribute significantly to polygenic dyslipidemia. [1] These variants can affect various components of lipid metabolism, including the synthesis, catabolism, and exchange of triglycerides within HDL and other lipoproteins, representing a systems-level integration of genetic influences on lipid homeostasis. Understanding this intricate genetic architecture is crucial for identifying individuals at risk and for developing targeted therapeutic strategies for lipid disorders.
Clinical Relevance
Section titled “Clinical Relevance”Understanding the factors that influence both high-density lipoprotein (HDL) cholesterol and triglyceride levels is crucial for assessing cardiovascular risk and guiding clinical management. While HDL cholesterol and triglycerides are often evaluated as distinct lipid parameters, genetic studies reveal an intricate, shared metabolic regulation that underscores their interconnected clinical implications. Insights from genome-wide association studies (GWAS) elucidate the genetic underpinnings affecting these lipid traits, offering avenues for improved risk stratification and personalized therapeutic strategies.
Genetic Insights into Interconnected Lipid Metabolism
Section titled “Genetic Insights into Interconnected Lipid Metabolism”Genetic research has identified several loci that influence both HDL cholesterol and triglyceride concentrations, highlighting the complex, interconnected nature of lipid metabolism. For instance, the geneGALNT2has been identified as a new locus associated with both HDL cholesterol and triglyceride levels.[1]This gene encodes a glycosyltransferase that could potentially modify a lipoprotein or receptor, suggesting a molecular mechanism by which it concurrently impacts these lipid traits.[4] Similarly, rare variants in ANGPTL4have been linked to both HDL and triglyceride concentrations, further emphasizing shared genetic regulation.[4] The protein encoded by ANGPTL3 is also recognized as a major regulator of lipid metabolism, indicating a broader family of genes with pleiotropic effects on lipid profiles. [4]These findings underscore that genetic predispositions to specific lipid profiles, particularly those affecting both HDL and triglyceride levels, are critical for understanding the overall dyslipidemic state.
Prognostic Value in Assessing Cardiovascular Risk
Section titled “Prognostic Value in Assessing Cardiovascular Risk”Genetic profiles that influence lipid levels, including both HDL and triglycerides, hold significant prognostic value for cardiovascular outcomes and disease progression. Research indicates that combining genetic risk profiles with traditional clinical risk factors, such as lipid values, age, body mass index, and sex, can improve the classification of coronary heart disease (CHD) risk.[2]While a genetic risk score for total cholesterol has shown robust associations with clinically relevant endpoints like hypercholesterolemia and intima media thickness, the individual lipid components, including HDL and triglycerides, contribute to this broader predictive landscape.[2]The independent prognostic importance of triglycerides is further supported by observations that nonfasting triglyceride levels are associated with an increased risk of cardiovascular events.[13]Consequently, understanding the genetic influences that concurrently modulate HDL and triglyceride levels provides a more comprehensive perspective on an individual’s long-term cardiovascular prognosis.
Personalized Approaches to Dyslipidemia Management
Section titled “Personalized Approaches to Dyslipidemia Management”The genetic understanding of lipid metabolism offers valuable clinical applications for risk stratification, personalized medicine, and prevention strategies for dyslipidemia. Identifying individuals with specific genetic variants that affect both HDL and triglyceride concentrations can improve the identification of high-risk populations, enabling earlier and more targeted interventions.[2] For example, specific genetic variants, such as rs2083637 in the LPL gene, have been shown to have differing effects on HDL levels between males and females, suggesting the need for sex-specific considerations in risk assessment and treatment selection. [2] Moreover, the elucidation of genes like GALNT2 and ANGPTL3that regulate lipid metabolism opens avenues for future therapeutic development and monitoring strategies, moving towards more tailored approaches in managing complex dyslipidemias and preventing cardiovascular disease.[4]
References
Section titled “References”[1] Kathiresan, S et al. “Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.”Nat Genet, vol. 40, no. 2, 2008, pp. 189-97.
[2] Aulchenko, Y. S. et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nature Genetics, vol. 40, no. 12, 14 Dec. 2008, pp. 1298-305.
[3] Burkhardt, R. et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 1, Jan. 2008, pp. 492-501.
[4] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nature Genetics, vol. 40, no. 2, 13 Jan. 2008, pp. 107-17.
[5] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 41, no. 1, Jan. 2009, pp. 47-55.
[6] Sabatti, C, et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 41, no. 1, 2009, pp. 35–46.
[7] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56–65.
[8] 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. 4, 2009, pp. 740–47.
[9] Kooner, JS et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, vol. 40, no. 2, 2008, pp. 149-51.
[10] Jiang, Xing-Chang, et al. “Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.”Journal of Clinical Investigation, vol. 103, no. 7, 1999, pp. 907–14.
[11] Isaacs, Anya, et al. “The - 514C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 8, 2004, pp. 3858–63.
[12] Phillipson, B. E., et al. “Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia.” New England Journal of Medicine, vol. 312, no. 19, 1985, pp. 1210–16.
[13] 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, Jan. 2008, pp. 132-42.