Glycerophosphorylcholine
Background
Section titled “Background”Glycerophosphorylcholine (GPC) is a water-soluble metabolite derived from the breakdown of phosphatidylcholine, a major phospholipid component of cell membranes. It is classified as a glycerophospholipid, characterized by a glycerol backbone, a phosphate group, and a choline head group. GPC is an important intermediate in the metabolic pathways involving phospholipids and choline.
Biological Basis
Section titled “Biological Basis”GPC plays a crucial role in various biological processes, including the synthesis and repair of cell membranes. It also serves as a source of choline, an essential nutrient involved in neurotransmission, particularly as a precursor for acetylcholine. The concentrations of various glycerophospholipids, including different types of phosphatidylcholines (e.g., PC aa C34:4, PC ae C36:4), are influenced by genetic variations. For instance, the single nucleotide polymorphism (SNP)rs174548 , located within a linkage disequilibrium block containing the FADS1 gene, is strongly associated with the levels of these glycerophospholipids in human serum. [1] The FADS1 gene encodes the fatty acid delta-5 desaturase, a key enzyme involved in the metabolism of long-chain polyunsaturated omega-3 and omega-6 fatty acids. [1] Individuals carrying the minor allele of rs174548 exhibit reduced efficiency of this enzyme, which correlates with lower concentrations of specific polyunsaturated fatty acid-containing phosphatidylcholines and their lyso-phosphatidylcholine derivatives.[1]
Clinical Relevance
Section titled “Clinical Relevance”Genetic influences on glycerophosphorylcholine and related glycerophospholipid levels can have clinical implications due to their fundamental roles in cellular function and metabolism. Alterations in lipid metabolism, as evidenced by the association of variants likers174548 with specific phosphatidylcholine concentrations, are relevant to understanding various metabolic conditions. [1]While the direct clinical impact of glycerophosphorylcholine itself is not extensively detailed in the provided studies, its position as a key metabolite within the broader lipid pathway suggests potential relevance as a biomarker or in the context of therapeutic interventions targeting membrane integrity or choline availability.
Social Importance
Section titled “Social Importance”The investigation of metabolites such as glycerophosphorylcholine through genome-wide association studies (GWAS) contributes significantly to understanding the complex genetic factors that shape human metabolism. Identifying genetic variants that influence circulating metabolite levels helps in defining individual metabolic profiles, or “metabotypes,” which can be foundational for personalized medicine approaches. This knowledge may aid in predicting disease risk and tailoring interventions based on an individual’s unique genetic and metabolic makeup.[1] By linking specific genetic variations to quantitative traits like metabolite concentrations, researchers gain deeper insights into fundamental biological processes and their impact on overall health.
Limitations
Section titled “Limitations”Methodological and Statistical Limitations
Section titled “Methodological and Statistical Limitations”Research into the genetic influences on glycerophosphorylcholine levels faces several methodological and statistical constraints that impact the robustness and interpretation of findings. A fundamental challenge in genome-wide association studies (GWAS) is the need for rigorous replication in independent cohorts to validate initial associations.[2]Without such external replication, findings remain exploratory and require further examination, risking effect-size inflation or false positives.[2] Additionally, the stringent statistical thresholds required for genome-wide significance, particularly when evaluating numerous metabolite traits or ratios, can mean that some true associations may not meet the prespecified significance level, potentially obscuring genuine genetic influences. [3]
The process of sample ascertainment can also introduce heterogeneity across studies, leading to discrepancies in results even for established loci. [4] This can arise from differences in participant recruitment, diagnostic criteria, or other study-specific protocols, making direct comparisons and meta-analyses more complex. While meta-analyses can increase statistical power by combining data from multiple cohorts, underlying heterogeneity can still limit the clarity and consistency of observed associations. [4]Therefore, careful consideration of study design and statistical rigor is essential for accurately identifying and interpreting genetic variants associated with glycerophosphorylcholine.
Generalizability and Phenotype Measurement
Section titled “Generalizability and Phenotype Measurement”A significant limitation in understanding the genetics of glycerophosphorylcholine is the generalizability of findings across diverse populations. Many large-scale genetic studies, including those contributing to the understanding of lipid metabolism, have predominantly focused on individuals of European ancestry.[3] While some efforts have been made to extend replicated findings to multiethnic cohorts, genetic associations and linkage disequilibrium patterns can differ substantially between ancestral groups, potentially limiting the direct applicability of findings to non-European populations. [4] This demographic bias necessitates further research in ethnically diverse populations to ensure that genetic insights are broadly relevant and to identify population-specific genetic factors.
Furthermore, the precise measurement and definition of glycerophosphorylcholine as a phenotypic trait present challenges. While direct metabolite concentrations are commonly used, the biological relevance of these single measurements might be enhanced by considering ratios of metabolites that are direct substrates and products of enzymatic conversions.[1] Utilizing such ratios can significantly reduce variance and increase the statistical power of association studies, suggesting that standard individual metabolite measurements might not fully capture the underlying biological activity or may introduce more noise, thereby impacting the clarity and strength of observed genetic associations. [1]
Environmental and Complex Genetic Interactions
Section titled “Environmental and Complex Genetic Interactions”The genetic architecture of glycerophosphorylcholine levels is likely influenced by a complex interplay of genetic, environmental, and lifestyle factors, many of which remain incompletely understood or unaccounted for. For instance, a single genetic variant likers174548 near the FADS1 gene may explain a notable portion (up to 10%) of the variance in certain glycerophospholipids, yet this implies a large proportion of variance remains unexplained. [1] This “missing heritability” suggests that numerous other genetic variants, including those with smaller effects or involved in non-additive interactions, as well as unmeasured environmental exposures, contribute significantly to the overall phenotype. [4]
Moreover, environmental or gene-environment interactions can confound observed associations, as lifestyle factors such as diet, physical activity, and medication use can profoundly influence metabolic profiles, including glycerophosphorylcholine levels.[4]The potential for sex-specific genetic effects also represents a critical, often unaddressed, limitation, as lipid values and disease prevalence are known to differ between males and females, implying that genetic risk profiles may also vary by sex.[5]Future research must integrate more comprehensive environmental data and consider complex interaction models to fully elucidate the genetic and non-genetic determinants of glycerophosphorylcholine.
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing an individual’s metabolic profile, including levels of glycerophosphorylcholine, a vital metabolite involved in cell membrane synthesis and various signaling pathways. These variants often affect genes that regulate lipid metabolism, glucose homeostasis, or cellular signaling, thereby indirectly or directly impacting the availability and utilization of glycerophosphorylcholine. Understanding these genetic influences provides insights into metabolic health and disease risk.
The rs376611885 variant is associated with the GCKR(glucokinase regulator) gene, which plays a pivotal role in regulating glucokinase, an enzyme essential for glucose phosphorylation in the liver and pancreas. Variants inGCKR, such as Leu446Pro, have been linked to plasma triglyceride levels, indicating its influence on lipid metabolism.[6] The GCKR gene region, including variants like rs780094 , has been widely associated with lipid concentrations, including triglycerides, suggesting that genetic variations in this area can modulate how the body processes fats and sugars. [7]Given glycerophosphorylcholine’s role as a precursor for phospholipids, which are fundamental components of cell membranes and are central to lipid metabolism, variations inGCKRcan impact the overall lipid environment and, consequently, the synthesis and turnover of glycerophosphorylcholine.
Variants like rs115829666 in GRIN2B and rs62338189 in DCLK2 are associated with genes primarily involved in neuronal function and development. GRIN2B encodes a subunit of the NMDA receptor, a critical component for synaptic plasticity and learning, while DCLK2is involved in microtubule dynamics and neuronal migration. Although not directly linked to glycerophosphorylcholine in some studies, the brain is exceptionally rich in phospholipids, including phosphatidylcholine, for which glycerophosphorylcholine is a precursor. Alterations in neuronal development or function due to these variants can influence the structural integrity and signaling capacity of neuronal membranes, thereby indirectly affecting the demand for and metabolism of glycerophosphorylcholine.
Other variants, such as rs77692382 and rs528045039 near MYCL and Y_RNA, rs4408378 near SLC6A15, rs144339260 in EPHA8, rs10433957 in CCSER1, and rs7545743 near JAK1 and rs6663882 near ERRFI1-DT, are associated with genes involved in diverse cellular processes. MYCL is an oncogene involved in cell growth, SLC6A15is an amino acid transporter,EPHA8 is a receptor tyrosine kinase involved in cell signaling, CCSER1is a coiled-coil serine-rich protein,JAK1 is a kinase critical for immune signaling, and Y_RNA and ERRFI1-DTare non-coding RNAs with regulatory roles. These genes, through their broad impact on cell proliferation, nutrient transport, signaling pathways, and gene expression, can indirectly influence the metabolic pathways that synthesize, transport, or utilize glycerophosphorylcholine. For instance, processes like inflammation regulated byJAK1can alter lipid metabolism and membrane remodeling, thereby affecting glycerophosphorylcholine levels.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs77692382 rs528045039 | MYCL - Y_RNA | level of T-cell surface glycoprotein CD1c in blood serum leukocyte quantity Red cell distribution width 1-oleoyl-GPC (18:1) measurement 1-stearoyl-GPC (18:0) measurement |
| rs376611885 | GCKR | glycerophosphorylcholine measurement 5alpha-androstan-3alpha,17beta-diol monosulfate (1) measurement |
| rs115829666 | GRIN2B | glycerophosphorylcholine measurement |
| rs4408378 | RPL6P25 - SLC6A15 | glycerophosphorylcholine measurement |
| rs144339260 | EPHA8 | glycerophosphorylcholine measurement |
| rs10433957 | CCSER1 | glycerophosphorylcholine measurement |
| rs7545743 | LINC01359, JAK1 | glycerophosphorylcholine measurement |
| rs6663882 | LINC01714, ERRFI1-DT | glycerophosphorylcholine measurement |
| rs62338189 | DCLK2 | glycerophosphorylcholine measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Chemical Identity and Classification
Section titled “Chemical Identity and Classification”Glycerophosphorylcholine is precisely defined as an endogenous organic compound and a key metabolite within the broader class of glycerophospholipids.[1]As a glycerophospholipid, it features a glycerol backbone linked to a phosphate group and a choline moiety. This structure positions it closely to phosphatidylcholines (PC), which are diacyl (two fatty acid residues, abbreviated ‘aa’) or acyl-alkyl (one acyl, one alkyl, abbreviated ‘ae’) forms of glycerophospholipids.[1]Glycerophosphorylcholine can be understood as a deacylated derivative, often referred to as a lyso-form, where one or both fatty acid chains typically found in phosphatidylcholines have been removed, leaving a single acyl or alkyl residue (abbreviated ‘a’ or ‘e’ respectively).[1] Its nomenclature reflects its fundamental chemical components, distinguishing it from more complex phospholipids by the absence of full fatty acid complements.
Biological Significance and Metabolic Context
Section titled “Biological Significance and Metabolic Context”As a naturally occurring substance in the body, glycerophosphorylcholine is an important component of serum, where its concentrations contribute to an individual’s overall metabolic profile.[1]It participates in various metabolic pathways, notably in phospholipid metabolism and choline homeostasis. The quantitative assessment of glycerophosphorylcholine levels serves as a valuable metabolic trait in research, allowing for the investigation of genetic influences on its concentration within human populations.[1] Variations in its serum levels can reflect underlying physiological states or responses to environmental factors, making it a relevant biomarker for understanding broader metabolic health.
Measurement Approaches and Research Applications
Section titled “Measurement Approaches and Research Applications”The precise measurement of glycerophosphorylcholine concentrations in biological samples, particularly fasting serum, is typically achieved using advanced analytical techniques.[1] A common and highly effective method involves targeted quantitative metabolomics platforms utilizing electrospray ionization (ESI) tandem mass spectrometry (MS/MS). [1]This approach allows for the accurate quantification of glycerophosphorylcholine alongside hundreds of other endogenous metabolites, providing a comprehensive metabolic fingerprint. In research, such as genome-wide association studies (GWAS), these measured concentrations are treated as phenotypic traits to identify genetic variations, like single nucleotide polymorphisms (SNPs), that influence metabolic pathways.[1]Furthermore, glycerophosphorylcholine concentrations, or their ratios with related metabolites, can serve as approximations of enzymatic activities or as proxies for established clinical parameters, aiding in the discovery and replication of associations with health outcomes.[1]
Biological Background of Glycerophosphorylcholine
Section titled “Biological Background of Glycerophosphorylcholine”Glycerophosphorylcholine (GPC) is a fundamental glycerophospholipid and a crucial intermediate in cellular metabolism. As a type of phosphatidylcholine (PC), GPC plays an essential role in maintaining cell membrane integrity, signaling pathways, and overall lipid homeostasis. Its structure, typically involving a glycerol backbone linked to a phosphate group and a choline head group, can vary based on the fatty acid residues attached to the glycerol moiety, which can be diacyl (aa), acyl-alkyl (ae), or dialkyl (ee) bonds, and characterized by the carbon chain length (C) and number of double bonds (y) in its side chains (Cx:y). [1] These structural variations influence its specific biological functions and metabolic fate within the body. [1]
Metabolic Pathways and Cellular Functions
Section titled “Metabolic Pathways and Cellular Functions”The synthesis and breakdown of glycerophosphorylcholine and related glycerophospholipids are integral to cellular function, primarily occurring through the Kennedy pathway. In this critical metabolic route, phosphatidylcholines are formed by linking two fatty acid moieties to a glycerol 3-phosphate, followed by a dephosphorylation step and the subsequent addition of a phosphocholine moiety.[1]This process is vital for membrane lipid biosynthesis, providing essential components for cellular membranes and various lipoprotein particles.[8] Beyond structural roles, these lipids are also involved in cell signaling and nutrient transport, highlighting their multifaceted importance in maintaining cellular viability and communication.
Fatty acid synthesis pathways are intimately connected to glycerophospholipid production, supplying the necessary building blocks. The human body can synthesize un- and monosaturated fatty acids with chain lengths up to 18 carbons, such as palmitic acid (C16:0), stearic acid (C18:0), and oleic acid (C18:1).[1]However, long-chain polyunsaturated fatty acids (PUFAs) like arachidonic acid (C20:4) must be produced from essential fatty acids such as linoleic acid (C18:2) in the omega-6 pathway or alpha-linolenic acid (C18:3) in the omega-3 pathway.[1] These PUFAs are then incorporated into glycerophospholipids, underscoring the dependency of complex lipid structures on both endogenous synthesis and dietary intake.
Genetic Regulation of Glycerophospholipid Composition
Section titled “Genetic Regulation of Glycerophospholipid Composition”Genetic mechanisms significantly influence the composition and levels of glycerophospholipids, with the fatty acid desaturase 1 (FADS1) gene playing a central regulatory role. Common genetic variants, particularly single nucleotide polymorphisms (SNPs) within theFADS1 FADS2 gene cluster, are strongly associated with the fatty acid composition in phospholipids. [9] Specifically, FADS1 encodes the delta-5 desaturase enzyme, which is crucial for converting eicosatrienoyl-CoA (C20:3) into arachidonyl-CoA (C20:4), a key precursor for many polyunsaturated glycerophospholipids. [1]
A polymorphism, such as rs174548 , within the FADS1 gene can reduce the catalytic activity or protein abundance of the delta-5 desaturase, thereby altering the availability of specific fatty acids for lipid synthesis. [1] This genetic variation leads to an accumulation of substrates like eicosatrienoyl-CoA (C20:3) and a reduction in products such as arachidonyl-CoA (C20:4). [1] Consequently, individuals carrying the minor allele of rs174548 exhibit lower concentrations of various phosphatidylcholines (PC aa C34:4, PC aa C36:4, PC aa C36:5, PC aa C38:4, PC aa C38:5, PC aa C38:6, PC aa C40:4, PC aa C40:5) and plasmalogen/plasmenogen phosphatidylcholines (PC ae C36:4, PC ae C38:4, PC ae C38:5, PC ae C38:6, PC ae C40:5) that contain four or more double bonds. [1]The ratio of product-to-substrate glycerophospholipid pairs, such as [PC aa C36:4]/[PC aa C36:3], serves as a highly sensitive indicator for the efficiency of theFADS1 enzyme’s metabolic activity. [1]
Pathophysiological Implications and Systemic Consequences
Section titled “Pathophysiological Implications and Systemic Consequences”Disruptions in glycerophosphorylcholine metabolism and overall lipid homeostasis are linked to various pathophysiological processes affecting multiple organs and systems. For instance, the liver, a central organ for lipid synthesis and metabolism, is particularly susceptible to these disruptions.[10]Imbalances in lipid profiles, including those related to phosphatidylcholines, are associated with conditions like nonalcoholic fatty liver disease (NAFLD), where enzymes like glycosylphosphatidylinositol-specific phospholipase D may play a role.[11]Altered glycerophospholipid composition can impair liver function and contribute to disease progression.
Beyond the liver, systemic consequences of aberrant glycerophospholipid metabolism extend to cardiovascular health. Genetic variations that influence lipid concentrations are known to contribute to polygenic dyslipidemia, a major risk factor for coronary artery disease.[3] Biomolecules such as phospholipid transfer protein (PLTP) and angiopoietin-like proteins (ANGPTL3 and ANGPTL4) are critical regulators of lipid transport and metabolism, influencing levels of high-density lipoproteins (HDL) and triglycerides. [12]Therefore, maintaining a balanced glycerophospholipid profile, influenced by both genetic factors and metabolic pathways, is crucial for preserving cardiovascular and broader metabolic health.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Glycerophospholipid Biosynthesis and Turnover
Section titled “Glycerophospholipid Biosynthesis and Turnover”The synthesis and breakdown of glycerophosphorylcholine and related phospholipids are fundamental processes for cellular function. Central to the biosynthesis of phosphatidylcholine is the Kennedy pathway, a multi-step process where two fatty acid moieties are sequentially incorporated into a glycerol 3-phosphate backbone, followed by a dephosphorylation step and the addition of a phosphocholine group.[1]The availability of specific fatty acids is critical for generating the diverse range of phospholipid species; for instance, long-chain polyunsaturated fatty acids are derived from essential precursors like linoleic acid (C18:2) and alpha-linolenic acid (C18:3) through pathways involving enzymes such asFADS1. [1] This intricate metabolic pathway ensures the constant replenishment of membrane components and supplies precursors for various lipid-derived molecules.
Metabolic Regulation and Lipid Transport
Section titled “Metabolic Regulation and Lipid Transport”Glycerophosphorylcholine and other phospholipids are key players in systemic lipid homeostasis, impacting the transport and metabolism of different lipid classes. The enzyme hepatic lipase, encoded byLIPC, is crucial in phospholipid metabolism; genetic polymorphisms, such as rs4775041 , can influence its substrate specificity, thereby affecting overall phospholipid and cholesterol levels. [1] Furthermore, the phospholipid transfer protein (PLTP) facilitates the exchange and transfer of phospholipids among lipoproteins, a process essential for the maturation of high-density lipoproteins (HDL) and for shaping plasma lipid profiles. [3] Dysregulation in these enzymatic activities or transport mechanisms can lead to significant imbalances in circulating lipids.
Genetic and Systems-Level Regulatory Mechanisms
Section titled “Genetic and Systems-Level Regulatory Mechanisms”The regulation of glycerophosphorylcholine metabolism is governed by a complex interplay of genetic factors and broader network interactions. Genetic variants can profoundly control metabolic pathways, as demonstrated by single nucleotide polymorphisms (SNPs) affecting enzymes likeLIPC, which can alter their function and subsequently influence various metabolite profiles.[1] These genetic influences contribute to the intricate crosstalk between pathways, where changes in one lipid class, such as phosphatidylethanolamines, can have cascading effects on interconnected metabolic networks, including the cholesterol pathway. [1] Such systems-level integration underscores how genetic variations in specific enzymes can lead to emergent properties within the overall metabolic landscape, impacting cellular and organismal physiology.
Disease-Relevant Mechanisms
Section titled “Disease-Relevant Mechanisms”Dysregulation in glycerophosphorylcholine and phospholipid metabolism is increasingly recognized as a contributing factor in several disease states, highlighting critical links between genetic predispositions and complex disorders. For example, polymorphisms inLIPC, such as rs4775041 , are associated with altered phospholipid and cholesterol levels, and also show weak associations with conditions like type 2 diabetes, bipolar disorder, and rheumatoid arthritis, suggesting a potential causal role in these pathologies.[1]Additionally, enzymes involved in general phospholipid processing, such as glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), have been investigated for their potential involvement in nonalcoholic fatty liver disease (NAFLD), indicating broader implications of phospholipid metabolism in liver health and disease progression.[13] A deeper understanding of these mechanistic links offers promising avenues for identifying therapeutic targets to manage lipid-related disorders.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Determinants and Lipid Metabolism
Section titled “Genetic Determinants and Lipid Metabolism”The levels of glycerophospholipids, including various phosphatidylcholines and related plasmalogen/plasmenogen phosphatidylcholines, are significantly influenced by genetic variations, particularly the minor allele of rs174548 . This single nucleotide polymorphism, located near theFADS1gene, is associated with reduced concentrations of these specific lipid metabolites, especially those characterized by four or more double bonds in their polyunsaturated fatty acid (PUFA) side chains.[1] The FADS1 gene cluster plays a crucial role in determining the fatty acid composition within phospholipids, underscoring a direct genetic link to fundamental lipid metabolism. [9]This genetic influence on glycerophospholipid profiles highlights a mechanism through which inherited factors can shape an individual’s metabolic landscape, impacting the availability of essential fatty acid derivatives.
Such genetically determined alterations in glycerophospholipid concentrations have implications for understanding comorbidities and associated conditions, particularly those involving dyslipidemia and cardiovascular health. For instance, the reduction in arachidonic acid and its lyso-phosphatidylcholine derivative with increasing copies of thers174548 minor allele suggests a direct impact on critical lipid signaling molecules. [1] Given that metabolite concentrations can serve as proxies for clinical parameters like blood cholesterol levels, these findings contribute to risk stratification by identifying individuals with specific genetic predispositions that may affect their lipid profiles and overall metabolic health. [1] Understanding these associations can help elucidate overlapping phenotypes in complex metabolic disorders.
Prognostic and Diagnostic Potential
Section titled “Prognostic and Diagnostic Potential”The identification of genetic variants influencing glycerophospholipid levels offers promising avenues for their utility as prognostic and diagnostic biomarkers in clinical settings. Measuring serum concentrations of these metabolites, alongside genetic screening for variants likers174548 , could provide insights into an individual’s metabolic state and risk for lipid-related disorders. [1]These metabolite profiles, reflecting the integrated activity of metabolic pathways and genetic predispositions, may serve as early indicators of metabolic dysfunction or progression toward adverse outcomes. Furthermore, the ability to approximate enzymatic activity through metabolite ratios could enhance the power of these biomarkers for precise diagnostic assessment.[1]
For patient care, integrating such genetic and metabolomic data could refine risk assessment beyond conventional factors. For example, individuals carrying the minor allele of rs174548 might be identified as having inherently lower levels of certain polyunsaturated glycerophospholipids, potentially guiding targeted monitoring strategies. [1]While further validation is needed, these biomarkers hold potential for predicting disease progression or treatment response in conditions where lipid metabolism plays a central role. This approach moves towards a more nuanced understanding of long-term implications by leveraging detailed molecular profiles.
Implications for Personalized Medicine
Section titled “Implications for Personalized Medicine”The understanding of how genetic variants influence glycerophospholipid concentrations paves the way for personalized medicine approaches in managing metabolic health. Identifying high-risk individuals based on their genetic predisposition, such as carriers of thers174548 minor allele with reduced polyunsaturated glycerophospholipids, could enable more targeted prevention strategies. [1]This involves tailoring interventions, whether dietary or pharmacological, to an individual’s unique metabolic profile, aiming to optimize lipid balance and mitigate disease risk. Such personalized strategies move beyond a one-size-fits-all approach, offering more effective patient care.
In the context of treatment selection, insights into an individual’s glycerophospholipid metabolism could inform therapeutic choices. For example, if specific genetic profiles are linked to differential responses to lipid-modulating therapies, this information could guide the selection of the most efficacious treatment for a given patient.[1]While the direct application to glycerophosphorylcholine-specific treatment selection requires further research, the broader principle of using genetic and metabolomic data to personalize interventions for conditions like dyslipidemia is a significant step forward.[3] This integrates genetic insights into clinical decision-making, optimizing outcomes for individuals with complex metabolic conditions.
References
Section titled “References”[1] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, 2008.
[2] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, 2007, p. 62.
[3] Kathiresan S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.
[4] 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. 11, 2008, pp. 2071-8.
[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, 2009, pp. 47-55.
[6] 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.
[7] 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.
[8] Vance JE. “Membrane lipid biosynthesis.” Encyclopedia of Life Sciences: John Wiley & Sons, Ltd: Chichester, 2001.
[9] Schaeffer L, et al. “Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.” Hum Mol Genet, 2006.
[10] Schadt EE, et al. “Mapping the genetic architecture of gene expression in human liver.” PLoS Biol, 2008.
[11] Chalasani N, Vuppalanchi R, Raikwar NS, Deeg MA. “Glycosylphosphatidylinositol-specific phospholipase d in nonalcoholic Fatty liver disease: A preliminary study.”J Clin Endocrinol Metab, 2006.
[12] Jiang XC, et al. “Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.”J Clin Invest, 1999.
[13] Yuan, Xin, et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” The American Journal of Human Genetics, vol. 83, no. 4, 2008, pp. 520-28.