Oxalate
Background
Section titled “Background”Oxalate, or oxalic acid, is a naturally occurring dicarboxylic acid found in various plants and produced as a metabolic byproduct in humans. It is typically excreted from the body via the kidneys.
Biological Basis
Section titled “Biological Basis”In the human body, oxalate is primarily formed from the metabolism of substances like ascorbic acid (Vitamin C) and glyoxylate, as well as absorbed from dietary sources. Oxalate readily binds with minerals such as calcium, forming calcium oxalate. This compound is poorly soluble and can crystallize in biological fluids.
Clinical Relevance
Section titled “Clinical Relevance”The most significant clinical relevance of oxalate lies in its role in the formation of kidney stones. Calcium oxalate stones are the most common type of kidney stone, resulting from the crystallization of calcium oxalate in the urinary tract.[1]Elevated levels of oxalate in the urine, a condition known as hyperoxaluria, significantly increase the risk of stone formation. Maintaining healthy kidney function, as indicated by biomarkers like serum creatinine and glomerular filtration rate (GFR)[2]is crucial for the efficient excretion of waste products, including oxalate.
Social Importance
Section titled “Social Importance”The prevalence of kidney stones associated with oxalate has considerable public health implications, leading to pain, medical interventions, and healthcare costs. Dietary intake of oxalate-rich foods can influence oxalate levels, making nutritional awareness important for individuals at risk. While genetic research has extensively explored variants associated with other metabolic biomarkers like uric acid and various cardiovascular traits[2], [3], [4], [5], [6], [7]the study of genetic predispositions to oxalate metabolism and calcium oxalate stone formation is an ongoing area of research.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The ability to comprehensively understand the genetic architecture of oxalate is constrained by the methodological and statistical limitations inherent in genome-wide association studies (GWAS). The moderate size of some cohorts limits the statistical power to detect genetic effects of modest size, increasing the likelihood of false negative findings and potentially missing genuine associations.[3] While family-based association tests offer robustness against population stratification, their power can be reduced as they primarily rely on information from individuals with heterozygous parents. [8]
Replication of findings across independent cohorts is crucial for validating genetic associations, yet many reported associations fail to replicate, possibly due to initial false positives, differences in study populations, or insufficient power in replication studies. [3] Furthermore, the accuracy of estimated genetic variance explained by identified variants depends on the precise estimation of phenotypic variance and heritability. [8]Inaccurate assumptions can inflate or deflate the perceived impact of discovered genetic variants, potentially misrepresenting their true contribution to oxalate levels.
Generalizability and Phenotype Characterization
Section titled “Generalizability and Phenotype Characterization”The generalizability of findings to broader populations is a significant limitation, as many studies are conducted on cohorts primarily composed of individuals of European descent or specific demographics like twins. [8] Recruitment biases, such as volunteer participation or DNA collection at later life stages, can introduce survival bias and further restrict the applicability of results to a wider, more diverse population. [8]This demographic specificity makes it challenging to infer how identified genetic influences on oxalate might manifest across different ancestries or age groups.
Accurate characterization of oxalate is critical, and variations in phenotype measurement, such as differences in blood collection time or confounding physiological states like menopausal status, can influence results and obscure true genetic associations.[8] Moreover, current GWAS platforms often cover only a subset of common genetic variations, potentially missing causal genes or providing an incomplete understanding of candidate genes due to insufficient SNP coverage. [9] While imputation methods are used to infer missing genotypes, they can introduce a degree of error, which might affect the precision and reliability of identified associations. [10]
Environmental Interactions and Unaccounted Variation
Section titled “Environmental Interactions and Unaccounted Variation”Genetic influences on oxalate may not act in isolation but rather in a context-specific manner, with their effects modulated by complex gene-environment interactions.[11]The absence of comprehensive investigations into these interactions means that some genetic associations could be overlooked or misinterpreted, as the full spectrum of environmental factors impacting oxalate levels is not fully captured. Therefore, a complete understanding of the genetic contribution to oxalate necessitates a thorough consideration of how genetic predispositions interact with environmental exposures.
Despite efforts to control for confounding factors like population stratification, residual confounding from unmeasured environmental influences or covariates can still impact observed associations. [8]Additionally, a focus on multivariable models might lead to missing important bivariate associations between specific genetic variants and oxalate.[2]These limitations highlight persistent knowledge gaps and underscore the need for further research to fully unravel the intricate interplay between genetic and environmental factors that contribute to oxalate.
Variants
Section titled “Variants”Variants in genes related to cellular transport, protein folding, and gene regulation can collectively influence metabolic processes, including the handling of oxalate. The_SLC23A3_ and _SLC23A1_genes are critical for vitamin C transport, a nutrient whose metabolism can impact oxalate levels._SLC23A3_ (Solute Carrier Family 23 Member 3) and _SLC23A1_(Solute Carrier Family 23 Member 1) encode sodium-dependent vitamin C transporters, essential for cellular uptake and distribution of ascorbic acid. The variantrs192756070 in _SLC23A3_may affect the efficiency of vitamin C transport, potentially altering cellular vitamin C concentrations and downstream metabolic pathways, which can indirectly influence oxalate production, particularly with high vitamin C intake. Similarly,rs33972313 , rs72552254 , and rs62385280 in _SLC23A1_could impact the activity or expression of this primary transporter, leading to altered vitamin C availability and affecting oxidative stress responses, which are factors in oxalate formation and excretion.[5], [12]Other variants are associated with fundamental cellular processes. _SIL1_(SIL1 Nucleotide Exchange Factor) plays a role in protein folding within the endoplasmic reticulum, acting as a cochaperone for the BiP protein, which is vital for maintaining cellular homeostasis. The variantrs17131975 could potentially disrupt this essential protein folding process, leading to cellular stress that might indirectly affect metabolic pathways, including those related to oxalate._CTNNA1_ (Catenin Alpha 1) encodes alpha-catenin, a protein crucial for cell-cell adhesion and the regulation of the actin cytoskeleton, linking cadherins to the cytoskeleton. Changes in cell adhesion and signaling, possibly influenced by rs62381198 , could impact the function of kidney epithelial cells, which are central to the regulation of oxalate excretion and the prevention of kidney stone formation._SCN1A-AS1_ is a long non-coding RNA (lncRNA) that acts as an antisense to the _SCN1A_gene, which encodes a voltage-gated sodium channel. The variantrs530371472 in _SCN1A-AS1_ may affect its regulatory activity, potentially influencing neuronal excitability or other cellular processes that could have systemic metabolic implications. [4], [6]Variants in regulatory and less characterized genes also contribute to the complex genetic landscape affecting metabolism. The region encompassing _MIR4431_ and _ASB3_ contains a microRNA and a gene involved in protein degradation, respectively. _MIR4431_ is a microRNA that regulates gene expression, while _ASB3_ (Ankyrin Repeat And SOCS Box Containing 3) is part of an E3 ubiquitin ligase complex. The variant rs182490914 in this region could impact gene expression regulation or protein turnover, thereby affecting metabolic pathways relevant to oxalate balance._MROH1_ (Maestro Heat-Like Repeat Family Member 1) is a less characterized gene, but proteins with similar repeats are often involved in protein-protein interactions and cellular scaffolding. The variant rs769256964 could influence general cellular architecture or signaling, potentially leading to downstream metabolic consequences that are not yet fully understood regarding oxalate._ASH1L_ (ASH1 Like Histone Lysine Methyltransferase) is an epigenetic regulator that modifies histones, thereby controlling gene expression by altering chromatin structure. The variant rs370184392 could affect _ASH1L_’s enzymatic activity, leading to widespread changes in gene expression profiles that might indirectly impact genes involved in oxalate transport, metabolism, or kidney function.[7], [13]Further genetic influences emerge from non-coding RNA regions and protein interaction domains. The intergenic region containing _LINC02879_ (Long Intergenic Non-Coding RNA 02879) and _MIR302F_ (MicroRNA 302F) highlights the importance of non-coding RNAs in genetic regulation. _LINC02879_ can modulate gene expression, while _MIR302F_ is a microRNA known for its role in stem cell maintenance and differentiation, influencing numerous cellular pathways. The variant rs1602735 within this region could affect the function or expression of these regulatory RNAs, leading to broad impacts on cellular metabolism and potentially influencing oxalate handling._LRRC1_(Leucine Rich Repeat Containing 1) encodes a protein with leucine-rich repeats, motifs commonly involved in protein-protein interactions and cellular signaling. Alterations in cellular communication or protein complex formation, potentially influenced byrs114547503 , could indirectly affect kidney function or metabolic pathways that contribute to oxalate levels or kidney stone formation.[14]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs192756070 | SLC23A3 | tartarate measurement tartronate (hydroxymalonate) measurement X-24432 measurement X-15674 measurement X-16964 measurement |
| rs33972313 rs72552254 rs62385280 | SLC23A1 | serum creatinine amount glomerular filtration rate vitamin C measurement glycerate measurement oxalate measurement |
| rs17131975 | SIL1 | oxalate measurement |
| rs62381198 | CTNNA1 | oxalate measurement |
| rs530371472 | SCN1A-AS1 | oxalate measurement |
| rs182490914 | MIR4431 - ASB3 | oxalate measurement |
| rs769256964 | MROH1 | oxalate measurement |
| rs370184392 | ASH1L | oxalate measurement N-acetylaspartate (NAA) measurement |
| rs1602735 | LINC02879 - MIR302F | oxalate measurement |
| rs114547503 | LRRC1 | oxalate measurement |
Biological Background of Oxalate
Section titled “Biological Background of Oxalate”Pathophysiology of Kidney Stone Formation
Section titled “Pathophysiology of Kidney Stone Formation”Kidney stones are a significant health concern, often arising from the crystallization of various substances within the urinary tract. An elevated serum uric acid level is directly associated with the formation of kidney stones due to the deposition of uric acid crystals in the collecting ducts of the kidney.[6]This process represents a disruption in normal homeostatic mechanisms, where imbalances in solute concentration can lead to pathological crystal formation. Beyond uric acid, dietary factors also play a role, with fructose consumption specifically identified as a risk factor for kidney stone development.[1]
Molecular Mechanisms of Uric Acid Homeostasis
Section titled “Molecular Mechanisms of Uric Acid Homeostasis”Uric acid, a primary end product of purine metabolism in humans, is largely regulated by a delicate balance of production, excretion, and reabsorption.[4]Unlike most mammals, humans lack the enzyme uricase, which typically converts uric acid into a more soluble and excretable form, leading to uniquely high serum uric acid concentrations.[12]The majority of daily urate disposal, approximately 70%, occurs via the kidneys, where complex transport mechanisms govern its levels in the blood.[12]The facilitative glucose transporterSLC2A9 (also known as GLUT9) has been identified as a critical protein in this process, demonstrating strong uric acid transport activity.[12] Interestingly, SLC2A9is also a known fructose transporter, which provides a potential molecular link between fructose intake and uric acid regulation.[12]
Genetic Regulation of Uric Acid Transport
Section titled “Genetic Regulation of Uric Acid Transport”Genetic factors significantly contribute to an individual’s serum uric acid levels, with heritability estimated to be as high as 63%.[4] Genome-wide association studies have identified variants within the SLC2A9gene that explain a notable portion of the variance in serum uric acid concentrations.[12] These genetic variations in SLC2A9are also associated with low fractional excretion of uric acid and an increased risk of gout, an inflammatory arthritis resulting from urate crystal deposition.[12] A common nonsynonymous variant in GLUT9has also been associated with serum uric acid levels, further underscoring the genetic influence on uric acid homeostasis.[6]
Cellular and Organ-Level Dynamics of Urate Excretion
Section titled “Cellular and Organ-Level Dynamics of Urate Excretion”The kidney plays a pivotal role in maintaining uric acid balance, primarily through processes occurring in the proximal renal tubules.[15] The SLC2A9gene, encoding a putative glucose transporter, is most strongly expressed in the kidney and liver, and also at lower levels in chondrocytes.[7] Specific splice variants of GLUT9, such as GLUT9ΔN, are exclusively expressed in the kidney and placenta, and are localized to kidney proximal tubule epithelial cells, which are the primary site of renal uric acid regulation and clearance.[6]This localized expression highlights the critical tissue-specific functions of these transporters in systemic uric acid control. Further studies using models likeXenopus laevisoocytes have confirmed the robust uric acid transport activity ofSLC2A9, providing insights into its cellular function. [12]
The provided context primarily discusses uric acid metabolism, transport, and its association with various health conditions, particularly focusing on theSLC2A9 (GLUT9) gene. There is no information provided in the given text regarding the pathways and mechanisms specifically related to oxalate. Therefore, a “Pathways and Mechanisms” section for oxalate cannot be generated based on the provided research materials.
References
Section titled “References”[1] Taylor, E. N., and G. C. Curhan. “Fructose consumption and the risk of kidney stones.”Kidney Int, 2008, 73(2):207–12.
[2] 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.
[3] Benjamin, E. J. et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, 2007, p. S10.
[4] Dehghan A et al. “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.” Lancet. 2008.
[5] Doring A et al. “SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.” Nat Genet. 2008.
[6] McArdle PF et al. “Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish.” Arthritis Rheum. 2008.
[7] Wallace C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet. 2008.
[8] Benyamin, B. et al. “Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels.”Am J Hum Genet, vol. 84, no. 1, 2009, pp. 60-65.
[9] 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, 2007, p. 55.
[10] 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.
[11] 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, vol. 8, 2007, p. S2.
[12] Vitart V et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.” Nat Genet. 2008.
[13] Li S et al. “The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.” PLoS Genet. 2007.
[14] Wilk JB et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Med Genet. 2007.
[15] Taniguchi, A., and N. Kamatani. “Control of renal uric acid excretion and gout.”Curr Opin Rheumatol, vol. 20, no. 2, 2008, pp. 192-7.