Blood Phosphate
Background
Section titled “Background”Phosphate is an essential mineral playing a critical role in numerous biological processes within the human body. As a major component of adenosine triphosphate (ATP), it is fundamental for energy storage and transfer. Phosphate is also crucial for the formation of bones and teeth, where it combines with calcium to create hydroxyapatite. Beyond structural roles, it is vital for cell membrane integrity, DNA and RNA synthesis, enzyme function, and maintaining proper pH balance in the blood. Circulating levels of phosphate in the blood, often referred to as serum phosphorus, are tightly regulated to ensure these diverse physiological functions are maintained.
Biological Basis
Section titled “Biological Basis”The body maintains blood phosphate levels through a complex interplay of dietary intake, intestinal absorption, bone metabolism, and renal excretion. The kidneys play a primary role in regulating phosphate balance, reabsorbing or excreting phosphate as needed to maintain homeostasis. Hormones such as parathyroid hormone (PTH) and vitamin D are key regulators of phosphate metabolism. Parathyroid hormone tends to decrease renal phosphate reabsorption, while vitamin D generally promotes phosphate absorption from the gut and reabsorption in the kidneys.[1]Genetic factors also contribute to individual variations in blood phosphate levels. For instance, specific genetic variants, such asrs10495487 , have been identified through genome-wide association studies as being associated with serum phosphorus levels.[2]Additionally, enzymes like alkaline phosphatase, which is involved in phosphate release, are influenced by genetic factors, with genes likeAkp2(in mice) and mutations affecting tissue-nonspecific alkaline phosphatase influencing its activity and related conditions like hypophosphatasia.[3]
Clinical Relevance
Section titled “Clinical Relevance”Monitoring blood phosphate levels is clinically important as both excessively high (hyperphosphatemia) and low (hypophosphatemia) levels can indicate underlying health issues. Hypophosphatemia can result from conditions like malnutrition, alcohol abuse, or excessive renal excretion, leading to symptoms such as muscle weakness, bone pain, and impaired heart and respiratory function. Hyperphosphatemia, often associated with kidney disease, can lead to complications such as secondary hyperparathyroidism, vascular calcification, and bone demineralization. Therefore, blood phosphate levels are routinely measured as a biomarker for kidney function, bone health, and overall metabolic status.
Social Importance
Section titled “Social Importance”The study of blood phosphate and its genetic determinants contributes significantly to public health by improving the understanding, diagnosis, and management of various diseases. Identifying genetic variants that influence phosphate levels can help pinpoint individuals at higher risk for conditions like chronic kidney disease, osteoporosis, and cardiovascular disease. This genetic insight can pave the way for personalized medicine approaches, allowing for earlier interventions or tailored treatments. Furthermore, understanding the genetic and physiological regulation of phosphate is crucial for developing new therapeutic strategies aimed at correcting phosphate imbalances, thereby improving patient outcomes and quality of life for a broad population.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The research into blood phosphate, similar to many genome-wide association studies (GWAS), has faced limitations due to moderate cohort sizes. This moderate sample size reduced statistical power, making the studies susceptible to false negative findings where genuine genetic associations with modest effect sizes might have been overlooked.[4] Conversely, the extensive multiple statistical testing performed across the genome concurrently increased the likelihood of false positive findings, meaning some reported associations may not represent true genetic effects and necessitate rigorous validation. [4]Consequently, the observed associations are prone to effect-size inflation, particularly for those findings that have not yet been independently replicated in diverse populations.
A critical constraint in these studies is the acknowledged need for external replication of findings in independent cohorts to definitively validate genetic associations for blood phosphate. Without such replication, the robustness and generalizability of identified associations remain uncertain, hindering a comprehensive understanding of their biological significance.[4] Additionally, the genotyping platforms utilized, such as the Affymetrix 100K gene chip, provided only partial coverage of the vast genetic variation across the human genome. [5]This incomplete genetic coverage could limit the detection of all relevant genetic variants influencing blood phosphate levels or impede the ability to replicate previously reported associations.
Generalizability and Phenotypic Nuances
Section titled “Generalizability and Phenotypic Nuances”The applicability of genetic findings for blood phosphate to broader populations is limited by the demographic characteristics of the study cohorts. Specifically, some study samples were neither ethnically diverse nor nationally representative, which raises questions about how observed genetic associations might translate or apply to other ethnic groups or the general population.[2] This lack of diversity can introduce cohort bias, meaning that genetic variants or their effects identified within these specific populations may not be universally consistent or have the same impact in individuals of different ancestries.
Furthermore, the precise interpretation of biomarker traits like blood phosphate can be intricate, even after extensive adjustments for known covariates. While researchers employ multivariable models to account for confounding factors, it remains possible that unmeasured or imperfectly characterized environmental, lifestyle, or physiological variables could still influence the observed genetic associations.[2]Blood phosphate levels are tightly regulated by complex interactions involving kidney function, parathyroid hormone, and vitamin D metabolism, and fully disentangling these intricate relationships from direct genetic effects in statistical models presents an ongoing challenge.
Environmental Interactions and Remaining Knowledge Gaps
Section titled “Environmental Interactions and Remaining Knowledge Gaps”A significant limitation in understanding blood phosphate genetics is the absence of comprehensive investigations into gene-environment interactions. Genetic influences on phenotypes are often context-dependent, with environmental factors playing a crucial role in modulating their expression and impact.[5]For blood phosphate, elements such as dietary intake, medication use, and other lifestyle variables likely interact with genetic predispositions, and without studying these complex interactions, a substantial portion of the trait’s variability remains unexplained, highlighting a key knowledge gap.
The genetic associations identified to date typically account for only a fraction of the total heritability observed for complex traits, including blood phosphate. This phenomenon, often referred to as “missing heritability,” suggests that numerous genetic variants with small individual effects, structural variations, rare variants, or complex gene-gene interactions may yet be undiscovered.[5]Consequently, a complete understanding of the genetic architecture influencing blood phosphate levels and its broad clinical implications necessitates further research into these more intricate genetic and environmental contributions.
Variants
Section titled “Variants”Genetic variations play a significant role in modulating blood phosphate levels, a critical aspect of mineral metabolism essential for bone health, energy transfer, and cellular signaling. Several genes and their specific variants are implicated in these complex regulatory pathways.
The FGF23gene (Fibroblast Growth Factor 23) encodes a hormone that is a primary regulator of systemic phosphate and vitamin D metabolism.FGF23acts predominantly on the kidneys to decrease phosphate reabsorption and suppress the production of active vitamin D, thereby lowering circulating phosphate levels. Variants such asrs7955866 in FGF23may influence the gene’s expression, stability, or the activity of the resulting protein, potentially altering the delicate balance of phosphate homeostasis and contributing to conditions of hypo- or hyperphosphatemia . Similarly, theALPLgene (Alkaline Phosphatase, Liver/Bone/Kidney type) produces an enzyme vital for bone mineralization, primarily by hydrolyzing pyrophosphate, a potent inhibitor of calcification. Genetic variations likers975000 , rs1697407 , and rs61778369 could affect ALPLenzyme activity, impacting skeletal integrity and indirectly influencing the availability of phosphate for mineralization. TheCASRgene (Calcium-Sensing Receptor) is crucial for maintaining calcium balance, but it also indirectly regulates phosphate through its influence on parathyroid hormone (PTH) secretion; variants such asrs1801725 , rs1979869 , and rs115230894 in CASRcan alter calcium sensing, leading to abnormal PTH levels and subsequent changes in renal phosphate handling.[6]
The ENPP3gene (Ectonucleotide Pyrophosphatase/Phosphodiesterase 3) encodes an enzyme that hydrolyzes extracellular nucleotides, yielding pyrophosphate. Pyrophosphate is a critical physiological inhibitor of soft tissue calcification, and its precise regulation indirectly affects phosphate metabolism and mineralization processes. Genetic variations, includingrs3883882 , rs9375819 , and rs7745372 within ENPP3, might alter the enzyme’s activity or expression, thereby influencing local pyrophosphate concentrations and overall systemic phosphate balance . Additionally, the genomic region spanningENPP3 and RPL15P9 (Ribosomal Protein L15 Pseudogene 9) contains variants such as rs12524635 and rs78231648 . These single nucleotide polymorphisms could affect regulatory elements influencingENPP3expression or other nearby genes, potentially contributing to individual variations in phosphate handling and overall mineral metabolism.[7]
Other genes involved in general cellular signaling and growth pathways can also have indirect impacts on metabolic regulation. For example, the RAP1GAP gene (RAP1 GTPase Activating Protein) is involved in inactivating RAP1 GTPases, which are important regulators of cell adhesion, proliferation, and differentiation. Genetic variations like rs1130564 , rs78915636 , and rs829416 could modulate RAP1GAPactivity, potentially affecting cellular responses relevant to endocrine signaling and indirectly influencing nutrient homeostasis, including blood phosphate . Similarly,RGS14 (Regulator of G-protein Signaling 14) plays a role in modulating G-protein coupled receptor signaling, a fundamental process in cellular communication. The rs12654812 variant in RGS14may alter the efficiency of these signaling cascades, potentially affecting various physiological processes that could, in turn, influence phosphate regulation. TheFGF6gene (Fibroblast Growth Factor 6), a member of the FGF family, is primarily recognized for its roles in muscle development and repair; while not a primary regulator of phosphate likeFGF23, variants such as rs11611403 in FGF6 could have broader implications for tissue growth and repair mechanisms that might indirectly intersect with mineral metabolism. [6]
The NBPF3gene (Neuroblastoma Breakpoint Family Member 3) belongs to a gene family whose precise functions are still under investigation, often implicated in neurodevelopmental processes. The variantrs60515836 in NBPF3 could represent a genetic alteration that influences the expression or function of this gene, potentially contributing to subtle variations in broader physiological or metabolic traits, which may include indirect effects on mineral balance . Furthermore, the genetic locus designated as FERRY3 includes variants such as rs2970818 and rs78869064 . These single nucleotide polymorphisms may be located within or near genes with less characterized functions concerning phosphate metabolism, but they could still contribute to the complex polygenic architecture underlying blood phosphate levels through mechanisms yet to be fully understood.[8]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs2970818 rs78869064 | FERRY3 | phosphorus measurement alkaline phosphatase measurement calcium measurement blood phosphate measurement |
| rs3883882 rs9375819 rs7745372 | ENPP3 | alkaline phosphatase measurement blood phosphate measurement |
| rs975000 rs1697407 rs61778369 | ALPL | alkaline phosphatase measurement blood phosphate measurement |
| rs1801725 rs1979869 rs115230894 | CASR | calcium measurement phosphate measurement blood phosphate measurement QT interval |
| rs12654812 | RGS14 | nephrolithiasis urinary system trait inflammatory bowel disease calcium measurement serum creatinine amount |
| rs60515836 | NBPF3 | alkaline phosphatase measurement blood phosphate measurement |
| rs11611403 | FGF6 | alkaline phosphatase measurement blood phosphate measurement |
| rs12524635 rs78231648 | ENPP3 - RPL15P9 | blood phosphate measurement |
| rs7955866 | FGF23 | blood phosphate measurement |
| rs1130564 rs78915636 rs829416 | RAP1GAP | alkaline phosphatase measurement blood phosphate measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Defining Serum Phosphorous as a Biomarker
Section titled “Defining Serum Phosphorous as a Biomarker”Blood phosphate, specifically referred to as serum phosphorous in research contexts, represents the concentration of inorganic phosphate ions circulating in the bloodstream. This biomarker is a crucial indicator of mineral balance and metabolic health. In studies such as the Framingham Heart Study, serum phosphorous is treated as a quantitative trait, identified by specific phenotype names like PHOSPHORUSMV2, to facilitate systematic analysis within large cohorts.[2] The precise measurement of serum phosphorous allows for its use in genetic association studies, where variations in its levels can be linked to genetic markers, providing insights into underlying physiological pathways.
Measurement and Operationalization in Research Studies
Section titled “Measurement and Operationalization in Research Studies”The measurement of serum phosphorous in research involves standardized laboratory procedures to ensure consistency and comparability across samples. For genetic association analyses, the raw serum phosphorous values are typically subjected to specific operational definitions and statistical adjustments. These adjustments often include multivariable regression models to account for confounding factors such as age, sex, and body mass index, among others, which can influence phosphate levels.[4] Such adjustments help to isolate the genetic contributions to serum phosphorous variation, enhancing the power and validity of gene discovery efforts. Furthermore, biomarkers like serum phosphorous may undergo transformations, such as natural log transformation, if their distribution is skewed, to meet the assumptions of statistical models. [4]
Contextual Significance and Related Concepts
Section titled “Contextual Significance and Related Concepts”Serum phosphorous serves as a significant biomarker within various conceptual frameworks, particularly in studies investigating kidney function and endocrine-related traits. Its levels are integral to understanding bone health, energy metabolism, and cellular function. The systematic classification of serum phosphorous as a biomarker trait, alongside other metabolic and physiological measures, enables researchers to explore complex interdependencies within the human body.[2]By analyzing its genetic determinants and associations with other health outcomes, researchers can gain a deeper understanding of its role in disease etiology and its potential as a target for therapeutic interventions, even when specific diagnostic criteria or severity gradations for phosphate dysregulation are not explicitly detailed in the immediate research context.
Biological Background
Section titled “Biological Background”The Essential Role of Phosphate in Human Physiology
Section titled “The Essential Role of Phosphate in Human Physiology”Phosphate is an indispensable mineral critical for numerous biological processes, serving as a fundamental building block for vital molecules such as adenosine triphosphate (ATP), the primary energy currency of cells. It is also an integral component of nucleic acids, DNA and RNA, and phospholipids that form cellular membranes. Beyond its molecular roles, phosphate provides structural integrity as a major constituent of bones and teeth, where it exists primarily as hydroxyapatite. Maintaining stable blood phosphate levels is therefore crucial for overall cellular function and skeletal health.
Hormonal and Enzymatic Control of Phosphate Homeostasis
Section titled “Hormonal and Enzymatic Control of Phosphate Homeostasis”The regulation of blood phosphate is a complex interplay involving various hormones and enzymes, primarily coordinated by the kidneys, bone, and intestines. Parathyroid hormone (PTH), a key biomolecule, plays a significant role in maintaining mineral balance, including phosphate, by influencing its excretion and reabsorption in the kidneys and mobilization from bone.[1]Another critical enzyme, alkaline phosphatase (ALP), particularly the tissue-nonspecific form, is deeply involved in phosphate metabolism and bone mineralization. Variations in plasma alkaline phosphatase activity have been observed, with genetic factors contributing to this variability.[9]
Genetic Influences on Blood Phosphate Levels and Related Enzymes
Section titled “Genetic Influences on Blood Phosphate Levels and Related Enzymes”Genetic mechanisms significantly contribute to the individual variability observed in blood phosphate levels. Genome-wide association studies (GWAS) have successfully identified specific genetic loci associated with serum phosphorus, such as the single nucleotide polymorphism (SNP)rs10495487 . [2]These genetic variations can impact the function or expression of genes involved in phosphate transport, cellular uptake, or regulatory pathways. For instance, theAkp2gene, which encodes alkaline phosphatase, has been shown to regulate serum alkaline phosphatase activity, suggesting a direct genetic influence on this enzyme’s levels and, consequently, on phosphate metabolism.[10]
Pathophysiological Consequences of Phosphate Dysregulation
Section titled “Pathophysiological Consequences of Phosphate Dysregulation”Disruptions in the tightly regulated balance of phosphate can lead to significant pathophysiological processes and disease states. A notable example is hypophosphatasia, a disorder characterized by impaired bone mineralization, which arises from specific missense mutations in the gene encoding tissue-nonspecific alkaline phosphatase.[11]These mutations lead to delayed transport of the enzyme, hindering its proper function and disrupting normal phosphate processing. Such genetic defects underscore how molecular alterations in key enzymes can result in systemic homeostatic disruptions, particularly affecting skeletal development and overall mineral balance. The genetic contribution to bone metabolism and the regulation of hormones like parathyroid hormone further highlight the interconnectedness of these systems in maintaining health.[1]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Enzymatic Modulation of Phosphate Metabolism
Section titled “Enzymatic Modulation of Phosphate Metabolism”Blood phosphate levels are intricately regulated through the action of various enzymes that catalyze the addition or removal of phosphate groups from biological molecules, influencing metabolic flux and cellular function. Key among these are the glucose-6-phosphatases, such as the protein encoded by theG6PC2gene, which plays a role in glucose metabolism by dephosphorylating glucose-6-phosphate.[12]This enzymatic activity is critical for glucose homeostasis, with polymorphisms inG6PC2being associated with fasting plasma glucose levels.[12]Similarly, alkaline phosphatases, including the tissue-nonspecific form, are crucial enzymes that remove phosphate groups from various substrates, and their activity in plasma is influenced by genetic and environmental factors.[3]The balance of these enzymatic actions directly impacts the availability and utilization of phosphate within cells and its systemic concentration.
Genetic and Transcriptional Control of Phosphate-Related Enzymes
Section titled “Genetic and Transcriptional Control of Phosphate-Related Enzymes”The expression and activity of enzymes involved in phosphate metabolism are tightly regulated at the genetic level, with specific genes influencing their synthesis and function. For instance, serum alkaline phosphatase activity is regulated by a chromosomal region containing the alkaline phosphatase 2 gene (Akp2). [3] Variations in genes like G6PC2have been identified as genetic determinants influencing metabolic traits, specifically fasting plasma glucose levels, through their impact on enzyme function.[12]The pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP) also demonstrates specific enzymatic characteristics, highlighting the diverse genetic control over phosphate-related metabolic processes.[13]These genetic predispositions contribute significantly to inter-individual variability in phosphate-related metabolic profiles and overall phosphate balance.
Post-Translational Regulation and Cellular Trafficking
Section titled “Post-Translational Regulation and Cellular Trafficking”Beyond gene expression, the activity and localization of phosphate-regulating enzymes are subject to post-translational modifications and cellular trafficking mechanisms. The proper transport of enzymes, such as tissue-nonspecific alkaline phosphatase, is essential for its function.[3]Missense mutations in this enzyme can lead to delayed transport, resulting in conditions like hypophosphatasia, which is characterized by impaired bone mineralization due to reduced alkaline phosphatase activity.[3]Such regulatory processes ensure that these enzymes are correctly folded, modified, and delivered to their active sites, thereby maintaining the precise control required for phosphate homeostasis and related metabolic pathways.
Systems-Level Interactions and Disease Pathways
Section titled “Systems-Level Interactions and Disease Pathways”Phosphate regulation is not isolated but integrated into broader physiological systems, with dysregulation leading to various disease states. The interplay between enzymatic activity, genetic predispositions, and systemic processes is evident in conditions like hypophosphatasia, where mutations affecting alkaline phosphatase trafficking result in skeletal abnormalities.[3]Furthermore, the connection between glucose-6-phosphatase function and fasting plasma glucose levels illustrates how phosphate-related enzymes are integral to metabolic health, with implications for type 2 diabetes.[12]Indirectly, markers of bone metabolism, such as osteocalcin, reflect systemic mineral balance, underscoring the interconnectedness of phosphate with bone health and other physiological processes.[4]
Clinical Relevance of Blood Phosphate
Section titled “Clinical Relevance of Blood Phosphate”Clinical Utility as a Biomarker
Section titled “Clinical Utility as a Biomarker”Blood phosphate, specifically serum phosphorus, serves as a routinely measured biochemical marker in extensive epidemiological studies, including the Framingham Heart Study.[2] These measurements are integral to characterizing an individual’s metabolic and physiological profile within large cohorts. [2]The consistent assessment of such biomarkers, often adjusted for various covariates, is fundamental for monitoring population health trends and identifying factors that influence overall well-being and disease states.[4]
Genetic Insights into Phosphate Homeostasis
Section titled “Genetic Insights into Phosphate Homeostasis”Genome-wide association studies have been instrumental in identifying genetic loci that influence circulating blood phosphate levels.[2]For instance, the single nucleotide polymorphismrs10495487 has been linked to serum phosphorus concentrations.[2]These genetic discoveries provide valuable insights into the complex biological pathways that regulate phosphate homeostasis, contributing to a deeper understanding of individual variability in phosphate levels.[2] Such findings can lay the groundwork for future research into personalized medicine approaches and targeted prevention strategies by elucidating genetic predispositions. [14]
Associations with Renal and Endocrine Health
Section titled “Associations with Renal and Endocrine Health”Blood phosphate levels are routinely assessed alongside other critical endocrine-related and kidney function biomarkers, such as serum creatinine, glomerular filtration rate (GFR), and serum calcium.[2] This comprehensive approach to biochemical evaluation is essential for understanding the intricate physiological interconnections within the body. [15]The collective analysis of these markers helps to identify systemic imbalances that can impact overall health and disease progression.
Research has demonstrated that markers of kidney function, including GFR, are significant predictors of cardiovascular outcomes and mortality across various populations.[2]While blood phosphate is intrinsically linked to renal health, its measurement within this broader panel contributes to a more complete picture for risk assessment.[2] This integrated perspective is crucial for identifying high-risk individuals and for developing holistic treatment and prevention strategies in clinical practice. [14]
References
Section titled “References”[1] Hunter, D., De Lange, M., Snieder, H., MacGregor, A.J., Swaminathan, R., Thakker, R.V., and Spector, T.D. (2001). Genetic contribution to bone metab-olism, calcium excretion, and vitamin D and parathyroid hormone regulation. J Bone Miner Res. 16, 371-378.
[2] Hwang, S. J. et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S10.
[3] Yuan, X., et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” American Journal of Human Genetics, vol. 83, no. 5, 2008, pp. 521-531.
[4] Benjamin, E. J. et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S11.
[5] Vasan, Ramachandran S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, suppl. 1, 2007, p. S2.
[6] Levy, D., et al. “Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness.”BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S3.
[7] Yang, Q., et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S9.
[8] Wilk, J. B., et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Medical Genetics, vol. 8, 2007, p. S8.
[9] Whitfield, J.B., and Martin, N.G. (1983). Determinants of variation in plasma alkaline phosphatase activity: A twin study. Am. J. Hum. Genet. 35, 978–986.
[10] Foreman, J.E., Blizard, D.A., Gerhard, G., Mack, H.A., Lang, D.H., Van Nimwegen, K.L., Vogler, G.P., Stout, J.T., Shihabi, Z.K., Griffith, J.W., et al. (2005). Serum alkaline phosphatase activity is regulated by a chromosomal region containing the alkaline phosphatase 2 gene (Akp2) in C57BL/6J and DBA/2J mice. Physiol. Genomics 23, 295–303.
[11] Brun-Heath, I., Lia-Baldini, A.S., Maillard, S., Taillandier, A., Utsch, B., Nunes, M.E., Serre, J.L., and Mornet, E. (2007). Delayed transport of tissue-nonspecific alkaline phosphatase with missense mutations causing hypophosphatasia. Eur. J. Med. Genet. 50, 367–378.
[12] Bouatia-Naji, N., et al. “A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels.”Science, vol. 320, no. 5879, 2008, pp. 1085–1089.
[13] Chen, W. M., et al. “Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.”J Clin Invest, vol. 118, no. 7, 2008, pp. 2620–2628.
[14] O’Donnell, C. J. et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S12.
[15] 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. 139–49.