Cholesterol In Large Hdl
Background
Section titled “Background”Cholesterol is an essential lipid molecule crucial for cellular function, hormone synthesis, and vitamin D production. It is transported throughout the bloodstream within various lipoprotein particles. High-density lipoprotein (HDL) is a class of lipoproteins often recognized for its role in reverse cholesterol transport, a process where it facilitates the removal of excess cholesterol from peripheral tissues and delivers it back to the liver. HDL particles vary in size and density, ranging from smaller, denser HDL3 to larger, less dense HDL2 subfractions. The concentration of cholesterol specifically within these larger HDL particles, referred to as “cholesterol in large HDL,” provides a more nuanced understanding of an individual’s lipid profile beyond total HDL cholesterol levels.[1]
Biological Basis
Section titled “Biological Basis”The dynamic processes governing the formation, maturation, and remodeling of HDL particles, including their size and cholesterol content, are intricately regulated by a complex interplay of genetic factors and enzymatic activities. Key proteins and enzymes implicated in HDL metabolism include apolipoprotein A-I (encoded byAPOA1), which is the primary structural protein of HDL, and lecithin-cholesterol acyltransferase (LCAT, encoded by LCAT), an enzyme vital for esterifying cholesterol within HDL, enabling the particles to grow and mature. Cholesteryl ester transfer protein (CETP, encoded byCETP) plays a significant role by facilitating the exchange of cholesteryl esters and triglycerides between lipoproteins, thus impacting HDL size and composition. Additionally, lipoprotein lipase (LPL) and hepatic lipase (LIPC) are crucial for the hydrolysis of triglycerides and phospholipids in lipoproteins, contributing to HDL remodeling. Genetic variations, such as single nucleotide polymorphisms (SNPs), in these and other genes, includingGALNT2, ABCA1, NR1H3, LIPG, and ANGPTL4, have been associated with measurable differences in HDL cholesterol levels and its subfractions, including cholesterol in large HDL. For example, the SNPrs4846914 in GALNT2 has been linked to HDL cholesterol levels, and rs7395662 in MADD-FOLH1 also shows an association. [2]
Clinical Relevance
Section titled “Clinical Relevance”Lipoprotein and lipid concentrations in the blood are recognized as heritable risk factors for cardiovascular disease (CVD). While higher total HDL cholesterol levels are generally associated with a reduced risk of CVD, the specific contribution of cholesterol within large HDL subfractions is an active area of research. Emerging evidence suggests that elevated levels of cholesterol in large HDL particles may confer particular protective benefits against the development of atherosclerosis and coronary artery disease (CAD). Investigating the genetic factors that influence cholesterol in large HDL can therefore contribute to improved methods for identifying individuals at varying levels of CVD risk, potentially paving the way for more precise risk stratification and personalized preventative or therapeutic strategies.[1]
Social Importance
Section titled “Social Importance”Cardiovascular diseases continue to be a leading global health concern, emphasizing the critical importance of understanding lipid metabolism and its genetic underpinnings for public health. Research focused on cholesterol in large HDL contributes to a broader comprehension of polygenic dyslipidemia, a complex trait where multiple genetic variants collectively influence an individual’s lipid profile. The identification of specific genetic markers and biological pathways associated with cholesterol in large HDL can inform the development of innovative therapeutic interventions and evidence-based lifestyle recommendations aimed at optimizing lipid profiles and mitigating the overall burden of CVD. This knowledge provides individuals and healthcare professionals with more granular insights into cardiovascular health and risk management.[3]
Limitations
Section titled “Limitations”Incomplete Genetic Architecture and Missing Heritability
Section titled “Incomplete Genetic Architecture and Missing Heritability”Despite identifying numerous genetic loci associated with HDL cholesterol, these common variants collectively explain only a small proportion of the total phenotypic variance. For instance, the identified genetic variants account for approximately 9.3% of the variance in HDL cholesterol concentrations. [1] Similarly, other studies indicate that the collection of associated loci explains around 6% of total variability. [2] This substantial gap highlights the presence of “missing heritability,” suggesting that a large portion of genetic and environmental influences on HDL cholesterol levels remains undiscovered, including potential contributions from rarer variants, structural variations, or epigenetic factors not captured by common SNP arrays. Consequently, the current understanding of HDL cholesterol regulation is partial, limiting the ability to fully predict individual lipid profiles or develop comprehensive polygenic risk scores.
Generalizability and Phenotypic Measurement Nuances
Section titled “Generalizability and Phenotypic Measurement Nuances”A significant limitation stems from the predominant focus on populations of European ancestry in the majority of the large-scale genome-wide association studies. [1] While some studies included diverse groups, such as Micronesian populations for specific loci [3] the broader findings may not be directly generalizable to other global populations with distinct genetic backgrounds and environmental exposures. Furthermore, inconsistencies in phenotype ascertainment and adjustment across different cohorts introduce heterogeneity; for example, some studies did not consider age2 as a covariate or had varying protocols for excluding individuals on lipid-lowering therapy or outliers in lipid distributions. [4] Such variations in measurement and adjustment can affect the comparability of results and potentially obscure or inflate true genetic effect sizes.
Challenges in Causal Inference and Complex Interactions
Section titled “Challenges in Causal Inference and Complex Interactions”The nature of genome-wide association studies means that identified SNPs indicate statistical associations rather than direct causation, necessitating further functional studies to pinpoint the precise causal variants and elucidate their underlying biological mechanisms. [1] The research acknowledges the potential impact of “non-additive interactions with other genetic variants or unaccounted environmental exposures” [3]which could contribute to observed discrepancies in replication and the remaining missing heritability. Moreover, it is important to recognize that not all genetic variants influencing related conditions, such as coronary artery disease, necessarily exert their effects through changes in lipid concentrations.[4] This suggests that focusing solely on HDL cholesterol or other lipid traits may not fully capture the complex genetic architecture of multifactorial diseases, thus limiting the direct translation of these genetic associations into comprehensive therapeutic strategies or precise risk stratification.
Variants
Section titled “Variants”Genetic variations play a significant role in determining an individual’s lipid profile, including the levels and characteristics of large high-density lipoprotein (HDL) cholesterol. These variants often influence the activity of enzymes and proteins involved in lipoprotein metabolism, leading to observable differences in cholesterol transport and cardiovascular risk.
Several key genes, including CETP, LIPC, and LPL, are central to the regulation of HDL cholesterol. The cholesteryl ester transfer protein (CETP), encoded by the CETPgene, facilitates the exchange of cholesteryl esters from HDL to triglyceride-rich lipoproteins and triglycerides in the reverse direction, profoundly influencing HDL particle size and concentration. Variants likers9989419 can alter CETP activity, often leading to higher HDL cholesterol levels when CETPactivity is reduced . Multiple common genetic variants across numerous loci contribute to this polygenic characteristic, with studies identifying associations between various single nucleotide polymorphisms (SNPs) and HDL cholesterol levels.[1] These common SNPs often act in concert, collectively affecting plasma levels of HDL cholesterol, underscoring the polygenic nature of this lipid trait. [5]
Further genetic investigations have revealed new genomic regions associated with HDL cholesterol, including a locus on chromosome 11 encompassing NR1H3 (also known as LXRA), and another region on chromosome 17. [2] Variants near MVK-MMAB and GALNT2 have also been specifically linked to HDL cholesterol levels. [4]The heritable nature of blood lipoprotein and lipid concentrations highlights the substantial role of inherited factors in determining an individual’s large HDL cholesterol profile .
Another significant gene, GALNT2, encodes polypeptide N-acetylgalactosaminyltransferase 2, an enzyme involved in O-linked glycosylation. [2]
Key Variants
Section titled “Key Variants”Demographic Modulators
Section titled “Demographic Modulators”Beyond genetic predispositions, several demographic factors are known to influence cholesterol in large HDL. Age is a significant modulator, with lipid concentrations often adjusted for age and age-squared in genetic association studies to account for its impact .
Biological Background: Cholesterol in Large HDL
Section titled “Biological Background: Cholesterol in Large HDL”High-density lipoprotein (HDL) cholesterol plays a crucial role in maintaining cardiovascular health, primarily due to its involvement in reverse cholesterol transport, a process that removes excess cholesterol from peripheral tissues and returns it to the liver for excretion or recycling.[4] Large HDL particles, in particular, are considered important mediators of this protective function. Understanding the intricate biological mechanisms governing cholesterol levels within these particles involves examining molecular pathways, genetic influences, and systemic physiological processes. The levels of HDL cholesterol are significantly influenced by an individual’s genetic makeup, with family studies indicating that approximately half of the variation in lipid profiles is genetically determined. [4] This complex genetic architecture contributes to the polygenic nature of dyslipidemia, where multiple genetic variants collectively impact lipid concentrations. [6]
The Role of HDL in Lipid Metabolism and Cardiovascular Health
Section titled “The Role of HDL in Lipid Metabolism and Cardiovascular Health”High-density lipoprotein cholesterol is inversely associated with the risk of coronary artery disease (CAD), meaning higher levels are generally protective.[4]Research indicates that a 1% increase in HDL cholesterol concentrations can reduce the risk of coronary heart disease by approximately 2%.[4]This contrasts with low-density lipoprotein (LDL) cholesterol, whose cumulative deposition in arteries is a primary underlying pathology of atherosclerosis, leading to impaired blood supply to vital organs.[4]
The balance between various lipoprotein-associated lipid concentrations is a consistent determinant of cardiovascular disease incidence globally.[4]While diet and physical activity influence individual lipid profiles, genetic factors are substantial contributors to the variation observed in HDL cholesterol and other lipid traits.[4]Genetic variants that influence lipid concentrations are also frequently associated with the risk of CAD, underscoring the critical link between lipid metabolism and cardiovascular health.[4]
Key Proteins and Enzymes in HDL Metabolism
Section titled “Key Proteins and Enzymes in HDL Metabolism”Several key biomolecules are integral to the synthesis, remodeling, and catabolism of HDL particles and their associated cholesterol. Apolipoprotein A-I (APOA1), a major protein component of HDL, is crucial for its structure and function, with studies showing increased APOA1 and phospholipid levels in transgenic mice expressing human APOA1. [7]Apolipoprotein C-III (APOC-III) is another significant player, synthesized in the liver and acting as an inhibitor of triglyceride catabolism.[6] A specific allele, GCKR P446L (rs1260326 ), has been associated with increased concentrations of APOC-III, highlighting a genetic influence on this regulatory protein. [6]
Enzymes like lecithin-cholesterol acyltransferase (LCAT) have a well-established role in lipid metabolism, particularly in the maturation of HDL particles and the esterification of cholesterol. [4] Rare genetic variants in LCAT are known to significantly affect lipid concentrations. [4] Angiopoietin-like 4 (ANGPTL4) is a mechanistic candidate gene whose protein product inhibits lipoprotein lipase, an enzyme critical for the breakdown of triglycerides.[6] A common variant, rs2967605 , in ANGPTL4 has been strongly associated with HDL cholesterol levels, illustrating how genetic variation in key regulatory proteins can impact HDL. [6]Other proteins like cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) are also central to the dynamic exchange and processing of lipids among different lipoprotein classes, including HDL.[4]
Genetic Regulation of Cholesterol Homeostasis
Section titled “Genetic Regulation of Cholesterol Homeostasis”The regulation of cholesterol homeostasis, including the levels of cholesterol in large HDL, is a complex process influenced by numerous genes and their regulatory elements. Common variants at multiple loci contribute to polygenic dyslipidemia, reflecting the intricate genetic architecture underlying lipid traits.[6] For instance, hepatocyte nuclear factor 4 alpha (HNF4A) and hepatocyte nuclear factor 1 alpha (HNF1A) are transcription factors implicated in cholesterol metabolism, with studies in null mice showing altered plasma cholesterol levels. [6] Although evidence connecting these genes to HDL or LDL cholesterol concentrations in humans has been modest, a specific HNF1AG319S variant has been linked to plasma lipoprotein variation.[6]
The gene for HMG-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis, is another critical regulatory point. Common single nucleotide polymorphisms (SNPs) inHMGCR have been shown to affect the alternative splicing of exon 13, which in turn impacts cellular cholesterol homeostasis and plasma cholesterol levels. [3] Variants in HMGCR have also been associated with the efficacy of pravastatin therapy, underscoring the clinical relevance of its genetic regulation. [8] Other genes, such as MLXIPL, encode proteins that activate motifs in promoters of triglyceride synthesis genes, whileMVK (mevalonate kinase) and MMAB (methylmalonic aciduria type B protein) are involved in cholesterol biosynthesis and degradation, respectively, and are regulated by the transcription factor SREBP2. [4]
Cellular Pathways and Tissue Interactions in Lipid Processing
Section titled “Cellular Pathways and Tissue Interactions in Lipid Processing”Lipid metabolism involves sophisticated cellular pathways and interactions across various tissues and organs. The liver plays a central role, not only in synthesizing APOC-III but also in processing lipoproteins through pathways like the WNT/beta-catenin signaling pathway, which has been functionally implicated in hepatic LDL processing. [6] Proteins such as PSRC1(proline/serine-rich coiled coil 1), also known as DDA3, are microtubule-associated proteins within this signaling pathway, andPSRC1 is abundantly expressed in the adult brain and fetal thymus. [9]
Macrophages contribute to lipid homeostasis by engulfing apoptotic cells, a process facilitated by phosphatidylserine receptors such as TIMD4 and HAVCR1 (TIMD1). [6] The gene HAVCR1 is also annotated as a target for the transcription factor TCF1, linking its cellular function to genetic regulation. [6] Furthermore, SORT1(Sortilin 1) is a nearby gene whose expression may be influenced by associated variants, mediating the endocytosis and degradation of lipoprotein lipase, thereby impacting overall lipid levels.[4] These interconnected cellular functions and tissue-specific expressions collectively regulate the dynamic processes of cholesterol metabolism and the characteristics of large HDL particles.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Regulation of Lipid Biosynthesis and Catabolism
Section titled “Regulation of Lipid Biosynthesis and Catabolism”The concentration of cholesterol in large HDL particles is intricately linked to core metabolic pathways governing lipid synthesis and breakdown. Key enzymes like mevalonate kinase, encoded byMVK, catalyze early steps in cholesterol biosynthesis, a process tightly regulated by transcription factors such as SREBP2. [10] Conversely, MMAB participates in a metabolic pathway responsible for cholesterol degradation, and its regulation is also linked to SREBP2. [4] The FADS1-FADS2-FADS3 gene cluster, associated with both HDL cholesterol and triglycerides, plays a critical role in the biosynthesis of polyunsaturated fatty acids, which are essential components of various lipids and lipoproteins. [1] Furthermore, angiopoietin-like proteins, specifically ANGPTL3 and ANGPTL4, serve as major regulators of lipid metabolism by influencing triglyceride levels and inhibiting lipoprotein lipase activity, thereby impacting the availability of fatty acids for lipoprotein assembly and remodeling.[4]
The dynamic flux of lipids through these pathways is critical for maintaining overall lipid homeostasis. For instance, MLXIPLencodes a protein that binds to and activates specific motifs in the promoters of triglyceride synthesis genes, directly affecting the production of these lipids.[4] Lecithin-cholesterol acyltransferase (LCAT) is another pivotal enzyme with a well-established role in lipid metabolism, catalyzing the esterification of cholesterol in HDL, a crucial step for cholesterol efflux from peripheral cells and the maturation of HDL particles. [4] Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids and cholesterol esters between lipoproteins, influencing HDL size and composition, with its increased expression leading to higher prebeta-HDL levels.[1] These interconnected processes collectively dictate the availability and processing of lipids that ultimately contribute to the composition and quantity of large HDL.
Transcriptional and Post-Translational Regulatory Mechanisms
Section titled “Transcriptional and Post-Translational Regulatory Mechanisms”The precise control of lipid metabolism, including the formation and remodeling of large HDL, relies heavily on sophisticated transcriptional and post-translational regulatory mechanisms. Transcription factors such as SREBP2 are central to regulating genes involved in cholesterol biosynthesis, including MVK and MMAB. [10] Similarly, hepatocyte nuclear factors like HNF4A and HNF1A are essential for maintaining hepatic gene expression and lipid homeostasis, with their dysregulation leading to altered plasma cholesterol levels. [1] These transcription factors orchestrate a complex network of gene expression, ensuring appropriate levels of enzymes and proteins necessary for lipid processing.
Beyond transcriptional control, post-translational modifications and protein interactions also exert significant influence. The TRIB1 gene, for example, encodes a protein belonging to the human tribbles family, which are known to control mitogen-activated protein kinase (MAPK) cascades. [11]These cascades are intracellular signaling pathways that can modulate the activity of various enzymes and transcription factors involved in lipid metabolism. Furthermore, specific genetic variations can impact protein function through mechanisms like alternative splicing; common single nucleotide polymorphisms (SNPs) inHMGCR are known to affect its alternative splicing, influencing cellular cholesterol homeostasis and plasma cholesterol levels. [3] Additionally, GALNT2, which encodes a glycosyltransferase, could potentially modify lipoproteins or their receptors, thereby altering their function or recognition by other cellular components. [4]
Dynamic Remodeling and Interconversion of Lipoproteins
Section titled “Dynamic Remodeling and Interconversion of Lipoproteins”The formation and function of large HDL involve a continuous process of dynamic remodeling and interconversion with other lipoproteins. LCATis a crucial enzyme in this process, esterifying free cholesterol on HDL particles, which drives the movement of cholesterol from the surface to the core of the HDL particle and enables its maturation and capacity for reverse cholesterol transport.[4] Defects in LCATactivity can lead to syndromes characterized by altered lipid concentrations and lipoprotein profiles.PLTPfurther contributes to HDL remodeling by facilitating the transfer of lipids between lipoproteins, particularly phospholipids and cholesterol esters, which is vital for maintaining the structural integrity and dynamic size changes of HDL particles.[1]
The apolipoprotein family, including APOA1, APOA4, and APOA5, plays a critical role in the structural integrity, metabolism, and functional properties of HDL. [8] For instance, APOC3is a key regulator of triglyceride metabolism, and a null mutation in this gene has been observed to confer a favorable plasma lipid profile and offer cardioprotection.[12] The hepatic cholesterol transporter ABCG8 is another component involved in cholesterol efflux and transport, influencing systemic cholesterol levels and potentially impacting the overall pool of cholesterol available for HDL. [1] These components collectively ensure the efficient loading, unloading, and modification of lipids within the HDL pathway, contributing to its diverse functions in lipid transport.
Systems-Level Integration and Disease Pathogenesis
Section titled “Systems-Level Integration and Disease Pathogenesis”The regulation of cholesterol in large HDL is not a solitary process but rather a highly integrated system involving extensive pathway crosstalk and network interactions. Genome-wide association network analyses have been employed to identify biological pathways enriched among genes associated with lipid levels, highlighting the complex interplay between various genetic factors and lipid metabolism.[8] For instance, the regulation by SREBP2 links isoprenoid and adenosylcobalamin metabolism, demonstrating how seemingly distinct pathways are interconnected at a mechanistic level. [10] The observed associations of the FADS1-FADS2-FADS3gene cluster with both HDL and triglycerides further exemplify this crosstalk, indicating a shared regulatory influence on fatty acid and lipoprotein metabolism.[1]
Dysregulation within these integrated pathways can significantly contribute to disease pathogenesis, particularly coronary artery disease. Genetic variants in genes likeANGPTL4have been strongly associated with HDL cholesterol concentrations, and their impact on lipoprotein lipase inhibition directly influences systemic lipid profiles and cardiovascular risk.[1] Similarly, variations in LCAT can considerably affect lipid concentrations, contributing to dyslipidemia. [4] Understanding these pathway dysregulations and identifying key therapeutic targets, such as the regulation of HMGCRthrough alternative splicing, offers avenues for interventions aimed at restoring lipid homeostasis and mitigating the risk of cardiovascular diseases.[3]
Clinical Relevance
Section titled “Clinical Relevance”Risk Assessment and Prognostic Value
Section titled “Risk Assessment and Prognostic Value”HDL cholesterol levels are widely recognized as heritable risk factors for cardiovascular disease ([1]). Specifically, low levels of HDL cholesterol are considered a significant risk factor for coronary heart disease ([4]). Integrating an individual’s genetic profile for HDL cholesterol with traditional clinical risk factors, such as age, body mass index, and sex, can enhance the precision of coronary heart disease risk classification ([13]). This combined approach offers a more comprehensive method for identifying individuals at higher risk for adverse cardiovascular outcomes and can inform personalized prevention strategies.
Genetic variants significantly influence HDL cholesterol concentrations, with specific single nucleotide polymorphisms (SNPs) likers4846914 in the GALNT2 gene being associated with decreased HDL cholesterol levels ([1]). The collective impact of such genetic markers contributes to a nuanced understanding of an individual’s predisposition to dyslipidemia and related conditions. The genetic architecture underlying HDL cholesterol is polygenic, with identified loci collectively explaining approximately 6% of its trait variability, underscoring the potential for genetic risk scores to improve prognostic accuracy in clinical settings ([14]).
Diagnostic Utility and Therapeutic Strategies
Section titled “Diagnostic Utility and Therapeutic Strategies”Measuring HDL cholesterol is a fundamental component of lipid panel testing, serving as a critical diagnostic tool for evaluating an individual’s cardiovascular risk profile ([4]). Clinicians utilize these levels to inform treatment decisions, which may include recommending lifestyle modifications or prescribing lipid-lowering pharmacotherapy. Ongoing monitoring of HDL cholesterol levels helps assess the efficacy of these interventions, although the direct clinical benefit of pharmacologically increasing HDL levels remains an area of active investigation.
Genetic insights into HDL cholesterol metabolism, including associations with genes such as CETP, LCAT, LPL, and ABCA1, provide a deeper understanding of the biological pathways involved in its regulation ([14]). While not yet standard in routine practice, this genetic information holds promise for advancing personalized medicine, potentially identifying individuals who may respond uniquely to certain lipid-modifying agents or who could benefit from early, targeted preventive measures based on their genetic predispositions.
Comorbidities and Genetic Associations
Section titled “Comorbidities and Genetic Associations”HDL cholesterol levels are frequently intertwined with a broader spectrum of metabolic conditions. For example, specific genetic variants like the GCKR P446L allele (rs1260326 ) have been associated with increased concentrations of APOC-III, a known inhibitor of triglyceride catabolism, illustrating the intricate connections within lipid metabolic pathways ([6]). This suggests that deviations in HDL cholesterol may not be isolated findings but rather indicators of more widespread metabolic dysregulation, necessitating a holistic approach to patient evaluation and management.
Multiple genetic loci have been consistently linked to HDL cholesterol concentrations, including those proximal to ABCA1, APOA1-APOC3-APOA4-APOA5, CETP, LIPC, LIPG, LPL, and GALNT2 ([1]). Additionally, novel associations have been identified in regions on chromosome 11 near NR1H3 and on chromosome 17 ([14]). These extensive genetic associations highlight the complex polygenic nature of HDL cholesterol regulation and its potential role in overlapping phenotypes, such as type 2 diabetes or altered beta-cell function, where genes influencing lipid metabolism often have broader physiological impacts.
References
Section titled “References”[1] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 2, 2008, pp. 182-9.
[2] Sabatti, C., et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.” Nat Genet, vol. 40, no. 1, 2008, pp. 190-195.
[3] Burkhardt, R., et al. “Common SNPs in HMGCR in Micronesians and Caucasians associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, vol. 28, no. 11, 2008, pp. 2078-85.
[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.
[5] 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, no. 6, 2007, pp. 1298-1303.
[6] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.
[7] Jiang, X., 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. Biol. Chem., N.D.
[8] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 40, no. 2, 2008, pp. 183-188.
[9] 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.
[10] Murphy, C., et al. “Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.” Biochem Biophys Res Commun, vol. 355, 2007, pp. 359–364.
[11] Kiss-Toth, E., et al. “Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.” J Biol Chem, vol. 279, 2004, pp. 42703–42708.
[12] Pollin, T. I., et al. “A genome-wide scan of serum lipid levels in the Old Order Amish.” Atherosclerosis, vol. 173, no. 1, 2004, pp. 89-96.
[13] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nature Genetics, vol. 41, no. 12, 2009, pp. 47-55.
[14] 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.