Atp

Adenosine triphosphate (ATP) is a ubiquitous and fundamental molecule within all known forms of life, serving as the primary energy currency of the cell. It is essential for powering virtually every cellular process, from metabolic reactions to mechanical work.

Biological Basis

Biologically, ATP functions as a rechargeable battery, storing and releasing energy through the breaking and forming of phosphate bonds. The majority of ATP synthesis occurs during cellular respiration, primarily within the mitochondria, where the energy released from the breakdown of nutrients like glucose is harnessed to add a phosphate group to adenosine diphosphate (ADP), forming ATP. When a cell requires energy, ATP is hydrolyzed, typically to ADP and inorganic phosphate, releasing a significant amount of energy that drives critical cellular functions such as muscle contraction, active transport of molecules across membranes, nerve impulse propagation, and the biosynthesis of complex macromolecules.

Clinical Relevance

The proper functioning of ATP production and utilization pathways is vital for human health. Impairments in ATP metabolism are implicated in a broad spectrum of clinical conditions. For instance, mitochondrial diseases, a group of genetic disorders, often result in defective ATP synthesis, leading to energy deficits that predominantly affect high-energy-demand organs like the brain, muscles, heart, and liver. Ischemic conditions, characterized by reduced blood flow and oxygen supply, also critically impact ATP levels, contributing to cellular damage and organ dysfunction. Furthermore, dysregulation of ATP pathways is a significant area of research in diseases such as cancer, neurodegenerative disorders, and metabolic syndromes, where altered energy metabolism plays a key role in disease progression.

Social Importance

The discovery and understanding of ATP’s role have profoundly influenced biological and medical science. It has provided a foundational framework for comprehending cellular physiology and pathology. Ongoing research into ATP and its metabolic pathways continues to yield insights into aging, exercise performance, and the development of new therapeutic strategies. Targeting specific enzymes or transporters involved in ATP metabolism holds promise for treating a wide array of human diseases, thereby impacting global health and enhancing the quality of life.

Limitations

Methodological and Statistical Constraints

The studies were often conducted with moderate sample sizes, which inherently limited the statistical power to detect genetic effects of modest magnitude, increasing the potential for false negative findings. ^[1] The extensive multiple testing performed in genome-wide association studies necessitated stringent significance thresholds, such as a conservative alpha level of 10-8, meaning that only SNPs explaining a substantial portion of phenotypic variation could be confidently identified. ^[2] This analytical challenge is further compounded by the acknowledgment that some moderately strong associations might still represent false-positive results, underscoring the critical need for independent replication in other cohorts to validate findings. ^[2]

Furthermore, the genetic variation coverage was partial due to the use of specific genotyping platforms, such as the Affymetrix 100K gene chip, which may not have captured all relevant genetic variants or adequately tagged regions within candidate genes. ^[2] This limitation could hinder the ability to comprehensively study specific candidate genes or to replicate previously reported associations if the original variants were not present on the array. ^[2] The application of different analytical methods, such as Generalized Estimating Equations (GEE) and Family-Based Association Tests (FBAT), often yielded distinct sets of top associated SNPs, complicating the interpretation and prioritization of genetic signals for follow-up. ^[2]

Phenotypic Characterization and Measurement Variability

The strategy of averaging phenotypic traits, such as echocardiographic dimensions, across multiple examinations was employed to enhance phenotype characterization and reduce regression dilution bias. ^[2] However, when these examinations spanned a prolonged period, sometimes up to twenty years, this approach might inadvertently mask age-dependent gene effects, as it assumes consistent genetic and environmental influences across a wide age range. ^[2] Moreover, changes in diagnostic equipment over such extended intervals could introduce systematic measurement error or misclassification, affecting the precision and comparability of the phenotypic data. ^[2]

Genetic variants may exert their influence in a context-specific manner, with associations potentially modulated by various environmental factors. ^[2] For instance, the associations of genes like ACE and AGTR2with left ventricular mass have been reported to vary according to dietary salt intake.^[2] The present studies generally did not undertake comprehensive investigations of such gene-environmental interactions, implying that important context-dependent genetic effects might remain unidentified and contributing to a less complete understanding of the observed genotype-phenotype relationships. ^[2]

Generalizability and Remaining Knowledge Gaps

The study cohorts were primarily composed of individuals of white European descent, largely middle-aged to elderly. ^[2] This demographic specificity limits the direct generalizability of the findings to younger populations or individuals from more diverse ethnic and racial backgrounds, emphasizing the necessity for replication in broader and more varied cohorts. ^[2] Furthermore, the timing of DNA collection, often at later examination cycles, potentially introduced a survival bias, as only participants who survived to those later exams were included in the genetic analyses. ^[1]

Despite observing modest to strong evidence of heritability for many of the investigated traits, none of the observed SNP-trait associations consistently achieved genome-wide statistical significance after rigorous correction for multiple testing. ^[2] This indicates that the common variants identified explain only a fraction of the total genetic variation, contributing to the phenomenon of “missing heritability”. ^[2] A substantial portion of the heritable component likely remains unexplained, potentially due to the influence of rare variants, complex gene-gene interactions, or limitations in the comprehensive coverage of genetic variation by the genotyping arrays. ^[2]

Variants

The _FAF1_gene, known as Fas-Associated Factor 1, plays a critical role in regulating programmed cell death, or apoptosis, a fundamental biological process essential for maintaining tissue health and development. Apoptosis is an energy-demanding process, requiring significant cellular ATP to execute its complex cascade of events. Variations likers115363550 in the _FAF1_gene could potentially influence the efficiency or timing of apoptosis, thereby affecting cellular ATP consumption and the overall metabolic balance within cells. Similarly, the_PFKP_gene encodes the platelet-type phosphofructokinase, a key enzyme that catalyzes a rate-limiting step in glycolysis, the primary metabolic pathway for generating ATP from glucose.^[3] As such, genetic variations such as rs2388595 within _PFKP_may alter the enzyme’s activity, directly impacting the rate of ATP production and the supply of cellular energy, which is particularly crucial for tissues with high glycolytic activity.^[4]

The _HBS1L_ and _MYB_ genes are located in close proximity and are highly significant for their roles in hematopoiesis, the process of blood cell formation, especially the development of red blood cells. _MYB_ acts as a proto-oncogene and a transcription factor, critical for the proliferation and differentiation of hematopoietic stem cells, while _HBS1L_ is involved in ribosome rescue and translational regulation. The genomic region encompassing these genes is frequently associated with variations, such as rs9389269 , that act as regulatory elements influencing gene expression, particularly impacting fetal hemoglobin levels and other red blood cell traits.^[5]Given that red blood cells are essential for oxygen transport, and oxygen is a crucial component of oxidative phosphorylation—the primary method of ATP production—variations affecting red blood cell development can indirectly influence systemic ATP availability and overall energy metabolism.^[6]

The _CYBRD1_ gene, also known as _DCYTB_, encodes a duodenal cytochrome B reductase, an enzyme vital for iron homeostasis. It facilitates the reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), a necessary step for iron absorption in the gut and its mobilization within cells. Iron is an indispensable component of many enzymes involved in oxidative phosphorylation, including the cytochromes within the mitochondrial electron transport chain, which directly produce the vast majority of cellular ATP . Therefore, variations likers114129368 , potentially located near _CYBRD1_, could influence its expression or function, thereby impacting iron availability and, consequently, the efficiency of mitochondrial ATP synthesis. While_RPL21P38_ is a pseudogene, its close genomic proximity to _CYBRD1_ suggests that _RPL21P38_ might be involved in regulatory interactions or linkage disequilibrium with functional variants impacting _CYBRD1_’s role in energy-related processes .

Key Variants

RS ID	Gene	Related Traits
rs115363550	FAF1	D-Glucose measurement atp measurement
rs9389269	HBS1L - MYB	erythrocyte volume liver fibrosis measurement platelet count guanine nucleotide exchange factor VAV3 measurement hemoglobin measurement
rs2388595	PFKP	pyruvate measurement platelet volume protein measurement phosphoenolpyruvic acid measurement D-Glucose measurement
rs114129368	CYBRD1 - RPL21P38	atp measurement

Classification, Definition, and Terminology

Definition and Classification of Natriuretic Peptides

Atrial natriuretic peptide (ANP), frequently identified by its N-terminal pro-form (NT-proANP), is precisely defined as a crucial biomarker within the broader category of Natriuretic Peptides.^[1]This family of peptides, which also encompasses B-type natriuretic peptide (BNP), plays a significant role in cardiovascular regulation and is systematically assessed as a biomarker trait in genetic and clinical investigations.^[1]The specific designation “N-terminal pro-atrial natriuretic peptide” clarifies that the measured entity is the stable N-terminal fragment of the prohormone, thereby providing a standardized nomenclature for both research and clinical applications.^[1]Its classification as a natriuretic peptide underscores its physiological function and its utility in evaluating cardiovascular health.

Operational Definitions and Measurement Approaches

The operational definition of atrial natriuretic peptide (ANP) in research studies typically involves its quantification at designated examination cycles, such as “Atrial natriuretic peptide exam 6” within the Framingham Heart Study.^[1] For comprehensive analysis, especially in genome-wide association studies, this trait is often subjected to adjustment for a wide array of covariates to mitigate confounding factors and enhance the accuracy of its association with genetic variants. ^[1]These multivariable adjustments for N-terminal pro-atrial natriuretic peptide include age, sex, body mass index (BMI), systolic blood pressure (SBP), hypertension treatment (HTN Rx), low-density lipoprotein (LDL), the ratio of total cholesterol to high-density lipoprotein (Total/HDL) cholesterol, diabetes status, left ventricular (LV) mass, and left atrial (LA) size.^[1] Such rigorous measurement and adjustment protocols are integral to ensuring the precision and comparability of ANP data across diverse analyses.

Clinical and Research Context

Atrial natriuretic peptide (ANP), particularly its N-terminal pro-form, serves as a vital biomarker in both clinical practice and research investigations, especially within the domain of cardiovascular disease and related metabolic traits.^[1]Its inclusion as a “biomarker trait” in genome-wide association studies (GWAS) underscores its utility in identifying genetic loci associated with various cardiovascular phenotypes.^[1]For instance, specific single nucleotide polymorphisms (SNPs), such asrs10507577 , have been evaluated for their association with ANP concentrations, indicating its role in uncovering genetic predispositions to a range of health outcomes. ^[1] This makes ANP a valuable tool for advancing the understanding of the genetic architecture of complex traits and for its potential application in diagnostic or prognostic strategies.

Biological Background

ATP as the Universal Energy Currency and its Metabolic Pathways

Adenosine triphosphate (ATP) serves as the primary energy currency within cells, driving a multitude of biological processes through its hydrolysis. Cellular metabolism generates ATP predominantly through two interconnected pathways: glycolysis and oxidative phosphorylation. Glycolysis, an anaerobic process, involves the breakdown of glucose to produce a small amount of ATP, a process initiated by enzymes such as hexokinase 1 (HK1), which is critical in red blood cells for maintaining their energy demands. ^[7] The activity of enzymes like PRKAG2, a subunit of AMP-activated protein kinase (AMPK), further modulates glucose uptake and glycolysis, playing a vital role in energy homeostasis and glucose metabolism.^[2]

Following glycolysis, if oxygen is available, pyruvate enters the mitochondria to fuel oxidative phosphorylation, which generates the vast majority of cellular ATP. This intricate process relies on the proper functioning of mitochondrial components, including protein translocase complexes like the mitochondrial SAM translocase complex, where variations in subunits such asSAMM50 can lead to mitochondrial dysfunction and impaired cell growth. ^[8]The efficient production and utilization of ATP are therefore fundamental to cellular survival, growth, and overall physiological function, with disruptions potentially impacting energy-intensive organs and tissues.

ATP in Cellular Signaling and Homeostasis

Beyond its role in energy transfer, ATP and its derivative, adenosine diphosphate (ADP), act as crucial signaling molecules that regulate various cellular functions, including platelet activation and aggregation. Platelets, essential for hemostasis, respond to extracellular ADP, which triggers a cascade of events leading to their activation and subsequent aggregation, a process characterized by “ADP-induced… platelet aggregation levels”.^[5] This signaling is critical for forming blood clots and preventing excessive bleeding.

ATP also plays a significant role in calcium trafficking within cells, particularly in muscle contraction and signaling. The ryanodine receptor (RYR2), for instance, is a key channel on the sarcoplasmic reticulum responsible for calcium release during cardiac muscle excitation-contraction coupling.^[2]Proper calcium handling, which is an ATP-dependent process, is essential for maintaining normal heart function, and disruptions inRYR2can lead to conditions such as exercise-induced polymorphic ventricular tachyarrhythmias.^[2]The precise control of ATP-mediated signaling is therefore vital for maintaining cellular and systemic homeostasis.

Genetic Regulation of Energy Metabolism and Cellular Function

Genetic mechanisms underpin the regulation of ATP production, utilization, and associated cellular functions, influencing health and disease susceptibility. Genes encoding enzymes involved in metabolic pathways, such asHMGCRin cholesterol synthesis, can exhibit common single nucleotide polymorphisms (SNPs) that affect gene expression or alternative splicing, thereby influencing metabolic outcomes.^[9] Similarly, variations in genes like HK1, which encodes hexokinase 1, have been associated with metabolic traits such as glycated hemoglobin levels, reflecting genetic influences on glucose metabolism.^[7]

Regulatory elements and epigenetic modifications also contribute to the intricate control of genes involved in energy homeostasis. For example, the ALPLlocus, encoding tissue-nonspecific alkaline phosphatase, contains cis-acting SNPs that can markedly affect gene expression in lymphoblastoid cells.^[8] Furthermore, genes like PRKAG2, which modulates glucose uptake and glycolysis, can have mutations associated with distinct clinical phenotypes such as cardiac hypertrophy, highlighting the profound impact of genetic variations on energy-related physiological processes.^[2]

Systemic and Pathophysiological Consequences of ATP Dysregulation

Dysregulation of ATP metabolism and signaling can have widespread systemic and pathophysiological consequences, affecting multiple organs and contributing to various disease states. For instance, impaired mitochondrial function, potentially indicated by variations in genes likeSAMM50, can compromise ATP production, leading to mitochondrial dysfunction that affects cell growth and overall tissue viability.^[8] In the heart, mutations in PRKAG2can lead to glycogen-filled vacuoles in cardiomyocytes, resulting in cardiac hypertrophy and conduction system disturbances, illustrating how defects in glucose metabolism and ATP modulation can manifest as severe cardiac pathologies.^[2]

Beyond direct energy roles, ATP-related pathways intersect with broader physiological systems. For example, the function of liver enzymes, such as alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST), reflects liver health, and their levels can be influenced by genetic variations and metabolic states.^[8]The systemic consequences of ATP dysregulation extend to conditions like metabolic syndrome and cardiovascular disease, where disruptions in energy balance, lipid metabolism, and inflammatory responses—all processes influenced by ATP—are central to disease progression.^[10]

Pathways and Mechanisms

Metabolic Regulation and Energy Homeostasis

Metabolic pathways are intricately regulated to maintain energy balance and cellular function, with several genes playing pivotal roles in diverse processes such as lipid metabolism, glucose homeostasis, and waste product excretion. For instance,HMGCR is a key enzyme in cholesterol biosynthesis, and its activity is precisely regulated, influencing its degradation rate and catalytic efficiency. ^[11] Similarly, FADS gene clusters, specifically FADS1 and FADS2, are crucial for the synthesis of polyunsaturated fatty acids, and variations within these genes are associated with the fatty acid composition in phospholipids, highlighting their role in lipid metabolic flux. ^[12]The regulation of glucose metabolism is also evident through genes likeHK1, which encodes a red blood cell-specific hexokinase isozyme, a critical enzyme in glycolysis, whose abnormalities can lead to energy-less red blood cells. ^[7]

Furthermore, solute carriers such as GLUT9 (also known as SLC2A9) and SLC22A12are essential for the transport of metabolites like urate and fructose, withGLUT9 acting as a determinant of substrate selectivity and SLC22A12functioning as a renal urate anion exchanger, both significantly influencing serum uric acid levels.^[13] Beyond these, genes like LPL, GALNT2, and the APOA1/C3/A4/A5cluster are implicated in the regulation of triglyceride and HDL cholesterol levels, whileNCAN-CILP2-PBX4 and APOB also influence LDL and HDL cholesterol, underscoring the complex, interconnected nature of lipid metabolism. ^[3] These pathways demonstrate how genetic variations can impact fundamental metabolic processes, affecting the synthesis, breakdown, and transport of crucial biomolecules, thereby maintaining or disrupting overall physiological homeostasis.

Genetic and Post-Translational Control of Protein Function

The precise control of gene expression and protein activity is fundamental to cellular regulation, involving mechanisms like alternative splicing and post-translational modifications. Alternative splicing is a critical regulatory mechanism, exemplified by HMGCR, where common genetic variants can affect the alternative splicing of exon 13, influencing protein isoforms and ultimately LDL-cholesterol levels. ^[9] Similarly, GLUT9 exhibits alternative splicing that alters its trafficking, impacting its function in substrate transport. ^[13] The APOB mRNA also undergoes antisense oligonucleotide-induced alternative splicing, leading to novel protein isoforms. ^[14]

Beyond splicing, proteins are subject to various post-translational modifications and regulatory interactions that fine-tune their function and stability. For instance, the oligomerization state of 3-hydroxy-3-methylglutaryl-CoA reductase, encoded by HMGCR, influences its degradation rate, providing a layer of post-translational control over enzyme abundance. ^[11] CPN1encodes arginine carboxypeptidase-1, a metalloprotease that protects against potent vasoactive and inflammatory peptides, demonstrating enzymatic activity as a regulatory mechanism.^[8] Additionally, PNPLA3, a liver-expressed transmembrane protein with phospholipase activity, is significantly upregulated during certain conditions, indicating a regulated response in lipid metabolism. ^[8]

Cellular Transport and Intracellular Signaling Dynamics

Cellular processes involve intricate signaling cascades and precise transport mechanisms that dictate cell behavior and maintain intracellular environments. GLUT9is a facilitative glucose transporter family member whose alternative splicing can alter its trafficking, highlighting the importance of proper localization for its function in substrate selectivity in the exofacial vestibule of SLC2A proteins.^[13] The SLC22A12gene encodes a renal urate anion exchanger, which plays a crucial role in regulating blood urate levels through active transport mechanisms.^[15]

Intracellular dynamics are further shaped by proteins like ERLIN1, a member of the prohibitin family, which defines lipid-raft-like domains of the endoplasmic reticulum, suggesting its involvement in membrane organization and signaling platforms. ^[8] The SAMM50 protein, a subunit of the mitochondrial SAM translocase complex, is essential for the importation and biogenesis of mitochondrial proteins, including metabolite-exchange anion-selective channel precursors, thereby profoundly affecting mitochondrial function. ^[8] Furthermore, PLEK (Pleckstrin) associates with plasma membranes and induces the formation of membrane projections, indicating its role in membrane dynamics and potentially in intracellular signaling cascades that mediate cellular shape and interactions. ^[12]

Integrated Physiological Networks and Disease Etiology

The interplay of multiple pathways forms integrated physiological networks, where dysregulation can lead to complex diseases, often revealing potential therapeutic targets. Genetic variants in genes like FTOare known to alter diabetes-related metabolic traits, influencing adiposity, insulin sensitivity, leptin levels, and resting metabolic rate, thereby contributing to the etiology of type 2 diabetes.^[7] Similarly, a common nonsynonymous variant in GLUT9is associated with serum uric acid levels, linking genetic predisposition to conditions like hyperuricemia and gout.^[16]Dyslipidemia, a major risk factor for cardiovascular disease, is influenced by common variants at numerous loci, includingLPL, GALNT2, APOA1/C3/A4/A5, NCAN-CILP2-PBX4, and APOB, demonstrating a polygenic contribution to this complex metabolic disorder. ^[17]

Mitochondrial dysfunction, potentially caused by variations such as the N-terminal Asp110Glu substitution in SAMM50, can impair cell growth and contribute to disease pathogenesis.^[8] Moreover, the NOS1 regulator NOS1APmodulates cardiac repolarization, indicating its involvement in cardiac function and potential relevance to cardiovascular diseases.^[4]The identification of such genetic associations with intermediate phenotypes and clinical outcomes through genome-wide association studies (GWAS) provides critical insights into affected pathways and offers opportunities for understanding disease-causing mechanisms and identifying novel therapeutic targets.^[12]

Clinical Relevance of Natriuretic Peptides

Clinical Applications and Biomarker Utility

Natriuretic peptides, including N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide, serve as valuable circulating biomarkers in clinical assessment.^[1]Their levels are routinely considered alongside a comprehensive set of cardiovascular risk factors, such as age, sex, body mass index (BMI), systolic blood pressure (SBP), hypertension treatment status, total and high-density lipoprotein (HDL) cholesterol levels, diabetes status, left ventricular (LV) mass, and left atrial (LA) size.^[1]These extensive adjustments are critical for accurate interpretation, especially given that a notable proportion of B-type natriuretic peptide levels can fall below typical assay detection limits.^[1] This careful consideration underscores their utility in diagnostic evaluations related to cardiac function and associated systemic conditions.

Genetic Associations and Risk Assessment

Research has identified significant genetic associations influencing natriuretic peptide concentrations, offering insights into their underlying biological regulation. Specifically,B-type natriuretic peptidelevels have been significantly associated with the single nucleotide polymorphismrs437021 . ^[1] Furthermore, brain natriuretic peptide on chromosome 1 is recognized as a “potential priority for follow-up” in genetic studies, indicating its established genetic component. ^[1]The identification of such genetic variants through methods like generalized estimating equations (GEE) and family-based association tests (FBAT) could enhance risk assessment strategies, enabling the identification of individuals genetically predisposed to altered natriuretic peptide levels.^[1]This genetic understanding holds promise for advancing personalized medicine approaches in the management of cardiovascular health.

Emerging Prognostic Indicators and Comorbidity Associations

Natriuretic peptides are recognized biomarkers whose levels correlate with several cardiovascular comorbidities, reflecting their integral role in cardiac and systemic health.^[1]The adjustment for factors such as hypertension, diabetes, left ventricular mass, and left atrial size in their assessment highlights their complex interplay with conditions affecting cardiac function and overall cardiovascular burden.^[1] While specific long-term prognostic values for these peptides were not explicitly detailed in the provided studies, the designation of brain natriuretic peptideas a “potential priority for follow-up” suggests ongoing investigation into its utility as a predictive indicator for future clinical outcomes and disease progression.^[1] This continued research aims to clarify their full prognostic capacity and potential for identifying individuals at higher risk.

References

[1] Benjamin, E. J. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S11.

[2] Vasan, R. S. et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, 2007.

[3] Sabatti, C, et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 40, no. 12, 2008, pp. 1394-402.

[4] 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, 2007.

[5] Yang, Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S12.

[6] Wilk, JB, et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S8.

[7] Pare, G. et al. “Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women’s Genome Health Study.”PLoS Genet, 2008.

[8] Yuan, X. et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, 2008.

[9] Burkhardt, R. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, 2009.

[10] Ridker, P. M. et al. “Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women’s Genome Health Study.”Am J Hum Genet, 2008.

[11] Cheng, H. H., Xu, L., Kumagai, H., Simoni, R. D. “Oligomerization state influences the degradation rate of 3-hydroxy-3-methylglutaryl-CoA reductase.” J Biol Chem, 1999.

[12] Gieger, C. et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, 2008.

[13] Augustin, R. et al. “Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.”J Biol Chem, 2004.

[14] Khoo, B. et al. “Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB.” BMC Mol Biol, 2007.

[15] Enomoto, A. et al. “Molecular identification of a renal urate anion exchanger that regulates blood urate levels.”Nature, 2002.

[16] McArdle, P. F. et al. “Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish.”Arthritis Rheum, 2007.

[17] Kathiresan, S. et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.