Urinary Ph
Introduction
Section titled “Introduction”Urinary pH refers to the measure of the acidity or alkalinity of urine, typically ranging from 4.5 (acidic) to 8.0 (alkaline), with an average around 6.0. It is a fundamental parameter in urine analysis, reflecting the body’s acid-base balance and the kidneys’ efficiency in maintaining homeostasis. Routine urine biochemistry measurements are widely used in clinical care.[1]
Biological Basis
Section titled “Biological Basis”The kidneys play a crucial role in regulating the body’s pH by selectively excreting excess acids or bases into the urine. This process involves complex mechanisms within the renal tubules, including the reabsorption of bicarbonate and the excretion of hydrogen ions and ammonium. Dietary intake significantly influences urinary pH; for instance, a diet rich in protein tends to produce more acidic urine, while a diet high in fruits and vegetables can lead to more alkaline urine. Urinary pH also affects the solubility of various compounds, such as uric acid, calcium oxalate, and phosphate, which are naturally present in urine.
Clinical Relevance
Section titled “Clinical Relevance”Monitoring urinary pH is clinically relevant for several reasons. It is a key diagnostic tool in the evaluation and management of kidney stone disease (nephrolithiasis), as different types of kidney stones form preferentially at specific pH ranges. For example, uric acid stones are more likely to form in acidic urine, while calcium phosphate stones tend to form in alkaline urine. Research has identified genetic loci associated with serum uric acid levels, such as theSLC2A9 and GLUT9genes, which influence urate reabsorption in the kidney.[1] Other genes, including ABCG2, SLC17A3, and SLC17A1, have also been linked to uric acid concentration and gout risk.[2]While these studies focus on uric acid levels, the connection to stone formation highlights the importance of urinary pH. Furthermore, urinary pH can influence the effectiveness and excretion of certain medications and may provide insights into metabolic conditions such as acidosis or alkalosis. It can also be a factor in urinary tract infections, as some bacteria can alter urine pH.
Social Importance
Section titled “Social Importance”Understanding urinary pH has social importance due to its implications for public health and individual well-being. It informs dietary recommendations for individuals at risk of kidney stones, guiding choices that can help prevent stone formation. Public awareness of the factors influencing urinary pH can empower individuals to make informed lifestyle decisions, contributing to better management of conditions related to kidney health.
Phenotypic Ascertainment and Measurement Limitations
Section titled “Phenotypic Ascertainment and Measurement Limitations”The ascertainment of phenotypic traits, such as urinary pH, often relies on single measurements, which may not adequately capture the dynamic nature or long-term average of the trait, potentially leading to misclassification or reduced precision in genetic association studies.[3]Similarly, the use of specific measurement methodologies or estimation equations, while sometimes necessary, can introduce inherent biases. For example, if urinary pH were estimated or measured using a method developed in a different population or with different analytical characteristics, it could compromise the accuracy and comparability of the results across studies.[3]Furthermore, the specificity of any biomarker, including urinary pH, as an indicator for a particular physiological process can be a significant limitation. Other traits like cystatin C, for instance, may reflect broader health risks beyond kidney function, suggesting that urinary pH could similarly be influenced by multiple, complex physiological pathways not directly targeted by the research.[3]The absence of more direct or comprehensive measures, such as using a single indicator like thyroid stimulating hormone (TSH) without free thyroxine levels, underscores the potential for incomplete characterization of the underlying biological state, which could impact the interpretation of genetic associations with urinary pH.[3]
Statistical Power and Replication Challenges
Section titled “Statistical Power and Replication Challenges”A significant limitation in genetic association studies for traits like urinary pH often stems from moderate cohort sizes, which can result in insufficient statistical power to detect genetic variants with modest effect sizes, leading to potential false negative findings.[4]Conversely, the extensive number of single nucleotide polymorphisms (SNPs) tested in genome-wide association studies (GWAS) introduces a substantial multiple testing burden. This increases the likelihood of reporting false positive associations, where observed significance may be due to chance rather than true biological relationships.[3]The absence of independent replication across diverse cohorts further limits the confidence in reported associations for urinary pH. Unreplicated findings, even those reaching statistical significance, may represent spurious results or be specific to the original study population.[3] Replication is critical for validating initial discoveries and distinguishing robust genetic signals from chance findings, as evidenced by meta-analyses showing that only a fraction of initial phenotype-genotype associations are consistently replicated.[4]Therefore, the true positive genetic associations for urinary pH remain provisional without external validation.
Generalizability and Population Homogeneity
Section titled “Generalizability and Population Homogeneity”The generalizability of findings concerning genetic associations with urinary pH is often constrained by the demographic characteristics of the study cohort. If a sample is predominantly composed of individuals of a specific ancestry, such as white individuals of European descent, the results may not be directly applicable to other ethnic or racial groups.[3] Population-specific genetic architectures and environmental exposures can lead to variations in allele frequencies and linkage disequilibrium patterns, meaning that genetic associations observed in one homogenous population may not hold true in others.
Furthermore, age-related biases can affect the applicability of findings, particularly if the cohort is largely confined to a specific age range, such as middle-aged to elderly participants.[4]Such cohorts may not accurately represent younger populations, where the genetic and environmental factors influencing urinary pH could differ. Additionally, the timing of DNA collection, if performed at later examinations, might introduce a survival bias, as only individuals who survived to those later time points are included, potentially skewing the genetic landscape of the study population.[4] These factors collectively limit the broader relevance of the findings to a more diverse and representative national population.
Analytical Scope and Unmeasured Influences
Section titled “Analytical Scope and Unmeasured Influences”The analytical approach employed in genetic studies of traits like urinary pH can introduce specific limitations. A primary focus on multivariable models, while important for accounting for known confounders, may inadvertently obscure significant bivariate associations between individual SNPs and the phenotype of interest.[3]Furthermore, conducting only sex-pooled analyses, often to manage the multiple testing burden, means that sex-specific genetic effects on urinary pH may remain undetected. Genetic variants that exhibit associations exclusively in males or females could be missed, thus providing an incomplete picture of the genetic architecture.[5] The scope of genome-wide association studies is also inherently limited by the coverage of genotyped SNPs. Relying on a subset of all known SNPs, such as those available in reference panels like HapMap, means that certain causal genetic variants or even entire genes may be missed if they are not adequately tagged by the assayed markers.[5]While studies may adjust for numerous potential confounders, the possibility of residual confounding from unmeasured environmental or lifestyle factors, or complex gene-environment interactions not fully explored, cannot be entirely ruled out. Although some studies investigate specific gene-by-environment interactions, the vast array of potential interactions often means many remain unexamined, representing a significant knowledge gap in understanding the full etiology of traits like urinary pH.[2]
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing a wide array of physiological processes, including those that indirectly impact urinary pH. While urinary pH is primarily regulated by the kidneys to maintain the body’s acid-base balance, specific genes and their variants can modulate kidney function, metabolic pathways, and immune responses, thereby affecting this critical biomarker. Understanding these genetic influences provides insights into individual predispositions to various health conditions and metabolic states.
Variations in genes like HLA-B and POU2AF1 can influence immune system regulation, which may have downstream effects on kidney function and overall metabolic homeostasis. The HLA-B Polymorphisms like rs9266195 could alter immune recognition, potentially contributing to autoimmune conditions that affect renal health and thus acid-base balance. Similarly, POU2AF1 (OCT2 coactivator) is vital for B-cell development and antibody production, linking rs12417556 to immune response modulation.[4]Dysregulation of immune processes can lead to inflammation or damage in the kidneys, impairing their ability to excrete acids or reabsorb bicarbonate, thereby influencing urinary pH.
Other variants, such as rs144495334 in MPPED2 and rs28459016 in TBCD, are associated with genes involved in fundamental cellular processes. MPPED2 encodes a metallophosphoesterase, an enzyme that can be involved in various metabolic pathways or cell signaling events, potentially affecting cellular metabolism within the renal tubules.[1] Alterations in these pathways could impact the production or handling of acidic or basic compounds. TBCD (Tubulin Folding Cofactor D) p In kidney cells, particularly those involved in filtration and reabsorption, efficient microtubule function is vital for maintaining cellular integrity and transport mechanisms, and variations like rs28459016 could subtly impair these functions, leading to changes in ion and acid-base excretion.
Further genetic variations in genes like WDR72, KALRN, and the non-coding RNA region BCL6-AS1 - LINC01991 underscore the diverse genetic landscape influencing physiological traits. WDR72 (WD Repeat Domain 72) is involved in various cellular processes, often mediating protein-protein interactions, and its variant rs551225 might affect structural or regulatory pathways within kidney cells, impacting their ability to regulate solute and water balance.[6] KALRN(Kalirin) is a Rho guanine nucleotide exchange factor (Rho-GEF) that regulates the actin cytoskeleton, essential for cell shape, motility, and intracellular transport. While known for neuronal roles, actin dynamics are crucial in all cells, including kidney podocytes and tubular cells, influencing filtration barrier integrity and reabsorptive capacity.[4] A variant such as rs6790058 could subtly alter these cellular functions. Lastly, the intergenic region BCL6-AS1 - LINC01991 and its variant rs2253944 pertain to long non-coding RNAs (lncRNAs), which are increasingly recognized for their roles in regulating gene expression, including those involved in development, metabolism, and disease. Such a variant could influence the expression of nearby or distant genes, thereby indirectly affecting kidney function and the regulation of urinary pH.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs9266195 | HLA-B | sodium measurement urinary ph measurement |
| rs144495334 | MPPED2 | urinary ph measurement |
| rs28459016 | TBCD | urinary ph measurement |
| rs12417556 | POU2AF1 | urinary ph measurement |
| rs551225 | WDR72 | urinary ph measurement |
| rs2253944 | BCL6-AS1 - LINC01991 | urinary ph measurement |
| rs6790058 | KALRN | red blood cell density urinary ph measurement |
Causes of Urinary pH Variation
Section titled “Causes of Urinary pH Variation”Urinary pH, a critical indicator of the body’s acid-base balance, is influenced by a complex interplay of genetic predispositions, dietary habits, metabolic processes, and various other physiological factors. The kidney plays a central role in regulating urinary pH by adjusting the excretion and reabsorption of acids and bases, a process significantly shaped by the transport mechanisms within renal tubules.
Genetic Determinants of Renal Acid-Base Handling
Section titled “Genetic Determinants of Renal Acid-Base Handling”Genetic factors exert a substantial influence on the kidney’s ability to regulate urinary pH, primarily through variations in genes encoding transporters involved in acid-base and anion exchange. For instance, single nucleotide polymorphisms (SNPs) in genes such asSLC2A9, ABCG2, and SLC17A3have been strongly associated with serum uric acid levels, which directly impacts the acidic load in urine.[2] Specifically, SLC17A3 encodes NPT4, a sodium phosphate transporter, while the closely locatedSLC17A1 encodes NPT1, a urate transporter expressed in the human kidney, both crucial for renal handling of urate.[2] Variants in the GLUT9gene can alter the ambient level of organic anions in the kidney, thereby affecting urate reabsorption and circulating urate levels, which in turn influences the concentration of acidic compounds excreted in urine.[7]The urate/anion transporterURAT1facilitates the exchange of anions for urate, with lactate being a preferred exchange ion, a process vital for reabsorbing filtered urate from urine in exchange for cytosolic organic anions.[7] Genetic variations affecting the efficiency or expression of these transporters, including URAT1, NPT1, and NPT4, can alter the balance of acidic and basic components in the urine. Such changes in the excretion and reabsorption profiles of organic acids and phosphate ions directly contribute to variations in urinary pH, reflecting the underlying genetic architecture governing renal acid-base homeostasis.
Dietary, Metabolic, and Environmental Factors
Section titled “Dietary, Metabolic, and Environmental Factors”Beyond genetic predispositions, several environmental and metabolic factors significantly contribute to the modulation of urinary pH. Uric acid, the end product of purine metabolism, is a major acidic component of urine, and its levels are primarily determined by endogenous synthesis, cell turnover, and renal excretion or reabsorption.[2]Humans inherently lack uricase, the enzyme responsible for converting uric acid into a more soluble and excretable form, meaning uric acid contributes directly to urinary acidity.[2]Consequently, diets rich in purines, found in certain foods, can elevate uric acid production, leading to a more acidic urine.[7]Other lifestyle and metabolic influences, such as alcohol consumption, are known risk factors for hyperuricemia, thus indirectly affecting the urinary acid load.[2]Tissue ischemia can also stimulate uric acid production through the upregulation of xanthine oxidase, further contributing to the acidic content of urine.[7]These factors, by modulating the total metabolic load of acidic compounds, necessitate renal adjustments in excretion, thereby impacting the overall urinary pH.
Gene-Environment Interactions and Clinical Modifiers
Section titled “Gene-Environment Interactions and Clinical Modifiers”The intricate relationship between genetic susceptibility and environmental exposures further complicates the regulation of urinary pH. Genetic predisposition, such as specific SNPs associated with urate levels, can interact with environmental factors, influencing the extent to which diet or lifestyle impacts urine composition.[2]For example, in individuals with hypertension, altered blood flow in the proximal tubule can favor urate reabsorption, potentially modifying the urinary acid burden.[7]Furthermore, the use of certain medications, particularly diuretics, is a recognized risk factor for hyperuricemia, indicating their role in altering renal handling of urate and other solutes.[2]Thiazide diuretics, for instance, are known to influence biochemical parameters, and by affecting electrolyte and water balance in the kidney, they can indirectly impact the acid-base environment of the urine. Age-related physiological changes also influence renal function, including the kidney’s capacity to manage acid-base balance, which can lead to shifts in baseline urinary pH over time.
Uric Acid Synthesis and Systemic Regulation
Section titled “Uric Acid Synthesis and Systemic Regulation”Uric acid is the final product of purine metabolism in humans, a process primarily determined by endogenous synthesis and cellular turnover.[2]Unlike many other species, humans lack the enzyme uricase, which typically converts uric acid into a more soluble and excretable form, leading to generally higher uric acid levels in the human body.[2] This metabolic pathway is influenced by factors such as dietary purine intake and purines released from damaged cells.[7]Molecular and cellular pathways play a significant role in modulating uric acid synthesis. For instance, in the liver, where a substantial amount of uric acid is synthesized, conditions like rare deficiency of glucose-6-phosphatase (Glycogenosis Type I) can lead to increased uric acid levels.[7]Variations in the uptake of glucose via theGLUT9protein might alter glucose-6-phosphate levels and thus modulate metabolism through the pentose phosphate shunt.[7]Augmented levels of phosphoribosyl pyrophosphate synthesis, potentially regulated by microRNAs that repress phosphoribosyl pyrophosphate synthetase 1, can consequently lead to increased hepatic production of uric acid.[7]Furthermore, tissue ischemia can stimulate uric acid production by upregulating xanthine oxidase activity.[7]
Renal Mechanisms of Urate Transport and Excretion
Section titled “Renal Mechanisms of Urate Transport and Excretion”The kidney plays a critical role in maintaining uric acid homeostasis through the balance of excretion and reabsorption, primarily within the renal tubules.[2]Urate transport mechanisms are predominantly active in the proximal tubular epithelium.[7] Key biomolecules involved in this process include transporters such as URAT1, which facilitates the reabsorption of filtered urate from the urine in exchange for cytosolic organic anions, with lactate being a preferred exchange ion.[7] Another critical transporter is GLUT9, which has two characterized isoforms highly expressed in the liver and distal kidney tubules, potentially in segments like the distal convoluted or connecting tubules.[7] In these distal nephron segments, which are relatively anaerobic, GLUT9’s role in glucose transport might alter the levels of lactate and other organic anions in the interstitium and neighboring proximal tubule cells.[7]These changes in ambient organic anion concentrations can subsequently affect urate reabsorption mediated byURAT1, thereby influencing circulating urate levels.[7] Other transporters like SLC17A1 (NPT1) and SLC17A3 (NPT4) are also implicated, with NPT4 localizing to the apical membrane of renal proximal tubule cells and NPT1shown to transport urate in model systems.[2]Renal reabsorption of urate can also be favored by reduced blood flow in the proximal tubule or localized ischemia, particularly in hypertensive individuals.[7]
Genetic Factors Influencing Urate Homeostasis
Section titled “Genetic Factors Influencing Urate Homeostasis”Genetic mechanisms significantly contribute to serum uric acid levels, with studies indicating a high heritability of approximately 63%.[2]Genetic variations in several genes have been identified that modulate uric acid concentration through their roles in synthesis or renal excretion. For instance, variants in theGLUT9 gene (SLC2A9) are strongly associated with serum uric acid levels.[7] Homozygotes for certain allelic variants in GLUT9can differ in serum uric acid by approximately 0.6 mg/dl, representing about 10% of mean levels.[7] A common nonsynonymous variant in GLUT9has been specifically associated with serum uric acid levels.[8] Other genetic loci also play a role. The Q141K variant (rs2231142 ) in the ABCG2gene is considered potentially causally related to uric acid levels.[2] Additionally, a missense SNP (rs1165196 T269I) in exon 7 of SLC17A1 and a SNP (rs1165205 ) in SLC17A3have shown genome-wide significant associations with uric acid levels.[2]These genetic variations influence the expression and function of key transporters and enzymes, impacting the delicate balance of uric acid production and elimination, and thus contributing to individual differences in circulating uric acid concentrations.[2]
Pathophysiological Implications of Urate Dysregulation
Section titled “Pathophysiological Implications of Urate Dysregulation”Disruptions in uric acid homeostasis can lead to several pathophysiological processes, with hyperuricemia being a significant concern. Hyperuricemia, characterized by elevated serum uric acid levels, is a known risk factor for gout, a painful inflammatory arthritis.[2]Beyond gout, hyperuricemia is also associated with a range of other conditions including obesity, hypertension, cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus.[2]The mechanisms linking elevated uric acid to these diseases are complex and not fully elucidated, but proposed pathways include enhanced renin release from the kidney leading to vasoconstriction and sodium retention, suppression of nitric oxide production, and endothelial dysfunction.[1]Uric acid is considered an important prognostic factor in hypertension and cardiovascular mortality in patients with prevalent cardiovascular disease.[7]Common risk factors for developing hyperuricemia and related conditions include obesity, hypertension, diuretic use, and alcohol consumption.[2]Understanding the molecular and genetic underpinnings of uric acid regulation is crucial for identifying new targets for intervention and improving clinical management of these widespread health issues.[7]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”The regulation of urinary pH is a complex process intricately linked to the body’s acid-base balance and the excretion of metabolic waste products, particularly uric acid. While urinary pH itself is a critical indicator, its underlying mechanisms often involve the precise handling of solutes like uric acid, which directly influences the concentration of titratable acids in the urine. Dysregulation in these pathways can lead to altered urinary pH, impacting the solubility and excretion of compounds such as uric acid, thereby contributing to the formation of kidney stones and other conditions.
Renal Urate Transport and Excretion Pathways
Section titled “Renal Urate Transport and Excretion Pathways”The kidney plays a pivotal role in maintaining uric acid homeostasis, which profoundly impacts urinary pH. Uric acid is the final product of purine metabolism in humans, and its levels are primarily determined by endogenous synthesis, cell turnover, and the efficiency of renal excretion and reabsorption.[2]The molecular mechanisms governing urate transport in the renal tubules, particularly the proximal tubules, are crucial for regulating circulating urate levels and, consequently, the amount of uric acid excreted in the urine. Key transporters includeGLUT9 (SLC2A9), URAT1 (SLC22A12), SLC17A1 (NPT1), SLC17A3 (NPT4), and ABCG2.[2] GLUT9is highly expressed in the liver and distal kidney tubules, and its variants are associated with serum uric acid levels.[7] In the kidney, GLUT9may influence uric acid levels through its role in renal excretion, potentially by altering the metabolism of glucose to lactate and other organic anions in distal nephron segments.[7] These organic anions are critical for the function of URAT1, a renal urate anion exchanger primarily found in the proximal tubule, which reabsorbs filtered urate from the urine in exchange for cytosolic organic anions like lactate.[7] Therefore, variations in GLUT9activity can modulate the availability of exchange ions, directly impacting urate reabsorption and the amount of uric acid remaining in the urine, thus affecting urinary pH.
Metabolic Interplay and Hepatic Regulation
Section titled “Metabolic Interplay and Hepatic Regulation”Beyond renal handling, systemic metabolic pathways significantly influence uric acid production, which in turn affects its urinary excretion and the resulting urinary pH. The liver is a major site of uric acid synthesis, and its metabolic state can dictate the overall purine load. For instance, a deficiency in glucose-6-phosphatase, as seen in Glycogenosis Type I, leads to increased uric acid levels.[7]This highlights how glucose metabolism is intertwined with purine metabolism, as variations in glucose uptake viaGLUT9can impact glucose-6-phosphate levels and modulate metabolism through the pentose phosphate shunt.[7]Increased activity in the pentose phosphate shunt can lead to augmented phosphoribosyl pyrophosphate synthesis, which directly fuels hepatic uric acid production.[7]Furthermore, dietary factors, such as fructose consumption, have been linked to hyperuricemia and are considered a causal mechanism for metabolic syndrome.[9]This metabolic interplay means that shifts in carbohydrate metabolism, particularly fructose processing, can elevate systemic uric acid levels, increasing the renal excretory burden and potentially lowering urinary pH due to higher concentrations of uric acid in the filtrate.
Molecular Regulation of Transporter Function
Section titled “Molecular Regulation of Transporter Function”The precise regulation of urate transporters at a molecular level is critical for maintaining uric acid balance and influencing urinary pH. TheGLUT9 protein, for example, exhibits alternative splicing that alters its trafficking, and it possesses a highly conserved hydrophobic motif in its exofacial vestibule that is a critical determinant of substrate selectivity.[10] These structural and functional properties dictate how efficiently GLUT9transports its substrates, including glucose and potentially fructose, thus impacting downstream metabolic pathways that influence urate levels. Genetic variations, such as common nonsynonymous variants inGLUT9, are associated with altered serum uric acid levels, demonstrating a direct link between gene regulation and physiological outcomes.[8] The interaction between different transporters and their substrates also provides a layer of molecular regulation. URAT1preferentially exchanges urate for lactate, meaning that the ambient concentration of lactate and other organic anions in the renal interstitium and proximal tubule cells can significantly alter urate reabsorption.[7]This allosteric control, where the availability of one molecule (lactate) influences the transport of another (urate), represents a key regulatory mechanism. Such intricate molecular interactions ensure dynamic control over urate excretion, which is vital for preventing the crystallization of uric acid in the urine, a process highly dependent on urinary pH.
Systems-Level Integration and Disease Pathogenesis
Section titled “Systems-Level Integration and Disease Pathogenesis”The regulation of urinary pH and uric acid metabolism is a prime example of systems-level integration, where multiple pathways and organs interact to maintain homeostasis. Pathway crosstalk between glucose metabolism and purine metabolism, mediated in part byGLUT9 in both liver and kidney, illustrates how systemic metabolic health influences renal function.[7]The emergent properties of these network interactions manifest as the overall serum uric acid level and the composition of the urine. For instance, in hypertensive individuals, reduced blood flow in the proximal tubule or localized ischemia can favor urate reabsorption, further demonstrating the complex interplay between cardiovascular health and renal urate handling.[7]Dysregulation in these pathways is directly linked to several disease-relevant mechanisms. Elevated serum uric acid (hyperuricemia) is a well-established risk factor for gouty arthritis, kidney stones, and is an independent predictor of cardiovascular disease and metabolic syndrome.[8]The molecular mechanisms linking uric acid to these conditions include enhanced renin release, vasoconstriction, sodium retention, suppression of nitric oxide production, and endothelial dysfunction.[11] Understanding these integrated pathways offers potential therapeutic targets, such as modulating GLUT9 or URAT1activity, to normalize uric acid levels and consequently manage urinary pH, thereby mitigating the risk of uric acid crystal deposition and associated pathologies.
References
Section titled “References”[1] Wallace C, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet. 2008;82(1):139-49.
[2] Dehghan, A., et al. “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.”Lancet, vol. 372, no. 9654, 2008, pp. 1827–34.
[3] Hwang SJ, et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Med Genet. 2007;8(Suppl 1):S10.
[4] Benjamin EJ, et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet. 2007;8(Suppl 1):S11.
[5] Yang, Q., et al. “Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study.”Metabolism, vol. 54, no. 11, 2005, pp. 1435–41.
[6] Melzer D, et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet. 2008;4(5):e1000072.
[7] Li, S., et al. “The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.”PLoS Genet, vol. 3, no. 11, 2007, p. e194.
[8] McArdle, P. F., et al. “Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish.”Arthritis Rheum, vol. 58, no. 9, 2008, pp. 2874-2881.
[9] Taylor, E.N., and G.C. Curhan. “Fructose consumption and the risk of kidney stones.”Kidney Int, vol. 73, no. 2, 2008, pp. 207–12.
[10] Augustin, R., et al. “Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.”J Biol Chem, vol. 279, no. 16, 2004, pp. 16229-16236.
[11] Johnson, R.J., et al. “Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?”J Am Soc Nephrol, vol. 16, no. 7, 2005, pp. 1909–19.