Argininate
Introduction
Section titled “Introduction”Argininate refers to a specific amino acid variant, namely the Glycine-to-Arginine change at position 25 (Gly25Arg), found in isoform I of theGLUT9 (also known as SLC2A9) gene. [1] This genetic variation is part of a broader set of polymorphisms within the GLUT9gene that have been significantly associated with serum uric acid levels in human populations.[1]
Biological Basis
Section titled “Biological Basis”The GLUT9gene encodes a putative glucose transporter highly expressed in the liver and distal kidney tubules.[1]These organs play crucial roles in maintaining systemic glucose and uric acid homeostasis. Studies have verified thatGLUT9transports glucose, and its two characterized isoforms are expressed in key metabolic tissues.[1] Variants within GLUT9significantly and comparably affect uric acid levels across the entire distribution of values.[1]The kidney, in particular, has a pivotal role in handling urate through various organic anion transporters, andGLUT9 is believed to be involved in this mechanism. [2] The Gly25Arg change, specifically in GLUT9isoform I, contributes to the genetic diversity within this transporter, potentially influencing its function or expression and, consequently, uric acid regulation.[1]
Clinical Relevance
Section titled “Clinical Relevance”Genetic variations within the GLUT9gene, including those in linkage disequilibrium with the region containing the Gly25Arg variant, are strongly associated with serum uric acid concentrations.[1] For instance, specific alleles like the G allele of rs6855911 have been shown to have a negative additive effect on uric acid levels, meaning they are associated with lower serum uric acid.[1]High uric acid levels (hyperuricemia) are a known risk factor for conditions such as gout, cardiovascular disease, and renal disease.[1] In some studies, individuals carrying at least one G allele for rs6855911 exhibited a significantly lower prevalence of hyperuricemia compared to those with only A alleles, suggesting a protective effect against this condition.[1] This association highlights GLUT9variants as important genetic determinants of uric acid metabolism, with direct implications for the risk of hyperuricemia and related health issues.[1]
Social Importance
Section titled “Social Importance”Understanding the genetic factors that influence uric acid levels, such as the variants withinGLUT9, holds significant public health importance. Uric acid is a common biomarker, and its dysregulation is linked to a spectrum of metabolic and cardiovascular diseases.[1]Identifying individuals genetically predisposed to higher uric acid levels or hyperuricemia allows for earlier risk assessment and potentially targeted preventive strategies. Furthermore, the robust association ofGLUT9variants with uric acid levels across diverse populations, including founder populations like Sardinians and more heterogeneous groups like the InCHIANTI cohort, suggests a general biological mechanism that could inform the development of novel therapeutic targets for managing hyperuricemia and preventing conditions like gout.[1]This genetic insight contributes to personalized medicine approaches by offering a deeper understanding of individual susceptibility to uric acid-related health problems.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Many genome-wide association studies (GWAS) often face limitations due to moderate cohort sizes, which can lead to insufficient statistical power to detect modest genetic associations, potentially resulting in false negative findings [3]
Other variants affect genes involved in transport and receptor signaling, indirectly influencing arginine metabolism and related traits. The_SLC22A1_gene, for instance, encodes an organic cation transporter that mediates the uptake and efflux of various endogenous and exogenous substances, including some guanidinium compounds structurally related to arginine. Variants likers112201728 and rs34130495 in _SLC22A1_ could alter the transport efficiency of these molecules, thereby influencing their cellular concentrations and downstream metabolic effects. _SLC39A8_ (rs13107325 ) is a zinc transporter, and zinc is an essential cofactor for numerous enzymes, including those potentially involved in arginine metabolism or its regulatory pathways. Changes in zinc transport could therefore indirectly modulate enzymatic activity. The_IGF2R_ gene, associated with rs80254170 , encodes the Insulin-like Growth Factor 2 Receptor, which plays a role in growth, development, and metabolism by binding IGF-2 and trafficking lysosomal enzymes. Alterations in_IGF2R_function can influence broader metabolic homeostasis, potentially impacting nutrient sensing and cellular responses that interact with arginine pathways.[4], [5]Beyond direct metabolic enzymes and transporters, variants in genes involved in general cellular regulation and signaling can also have broad impacts. _CELA2B_ (rs3737704 ) encodes a chymotrypsin-like elastase, a protease that breaks down proteins and peptides. Variations here might affect the processing of arginine-containing peptides or proteins, influencing their half-life and biological activity._DNAJC16_ (rs6667064 ), a DnaJ homolog, functions as a chaperone protein, assisting in the proper folding and assembly of other proteins, including enzymes. Variants in chaperones can broadly affect the stability and function of numerous cellular proteins, including those involved in arginine-related pathways._GRIN2B_ (rs12582333 ) encodes a subunit of the NMDA receptor, a critical component of synaptic plasticity in the brain. Given arginine’s role as a precursor for nitric oxide, a neurotransmitter, variations in_GRIN2B_ could influence neuronal signaling and responses to nitric oxide. Furthermore, non-coding RNAs such as _RNU6-633P - LINC01290_ (rs137938669 ) and _SLC8A1-AS1_ (rs80169023 ) regulate gene expression. _RNU6-633P_ is a small nuclear RNA, while _LINC01290_ and _SLC8A1-AS1_are long intergenic and antisense non-coding RNAs, respectively. These non-coding RNAs can influence the transcription, stability, or translation of target genes, including those involved in metabolic regulation or cellular processes that indirectly intersect with arginine metabolism, such as calcium signaling regulated by_SLC8A1_. [4], [6]## Signs and Symptoms
Manifestations of Altered Lipid Metabolism
Section titled “Manifestations of Altered Lipid Metabolism”The clinical presentation associated with ‘argininate’ primarily involves alterations in circulating lipid concentrations, which, in early stages, are typically asymptomatic but can progress to more overt signs of dyslipidemia.[7]Severe or chronic elevations, particularly of cholesterol or triglycerides, may lead to physical manifestations such as xanthomas (fatty deposits under the skin) or xanthelasmas (yellowish plaques on eyelids), though these are less common. The patterns of presentation vary, with some individuals exhibiting consistently high low-density lipoprotein (LDL) cholesterol, while others might show elevated triglycerides or low high-density lipoprotein (HDL) cholesterol, each representing a distinct clinical phenotype.
Measurement approaches for evaluating this aspect of ‘argininate’ rely fundamentally on a fasting lipid panel, which objectively quantifies total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in the blood.[7] These biochemical markers are crucial diagnostic tools, providing a quantitative assessment of the metabolic state and serving as primary biomarkers for identifying individuals with altered lipid profiles. The results are interpreted against established measurement scales to determine the severity and specific type of dyslipidemia, guiding subsequent clinical management and providing insights into inter-individual variation.
Cardiovascular Implications and Risk Assessment
Section titled “Cardiovascular Implications and Risk Assessment”A significant clinical presentation linked to ‘argininate’ is an elevated risk of coronary artery disease (CAD), which can range in severity from asymptomatic arterial plaque buildup to acute, life-threatening events like myocardial infarction.[7]Common symptoms, if present, include angina (chest pain), shortness of breath, and fatigue, particularly with exertion, reflecting impaired blood flow to the heart. The overall presentation patterns can be highly variable, with some individuals experiencing silent ischemia while others present with classic symptoms, often influenced by the extent and location of atherosclerotic plaques.
Diagnostic tools for assessing CAD risk and progression include non-invasive methods such as electrocardiography (ECG), echocardiography, and stress testing, which evaluate heart function and blood flow, alongside invasive procedures like coronary angiography to visualize arterial blockages. [7]These objective measures, combined with subjective symptom reporting, help in characterizing the clinical phenotype and assessing severity ranges. The identification of specific genetic loci influencing lipid levels and CAD risk aids in a more precise diagnostic assessment and offers prognostic indicators for long-term cardiovascular health.[7]
Variability and Diagnostic Significance
Section titled “Variability and Diagnostic Significance”The clinical presentation of ‘argininate’-related conditions exhibits considerable inter-individual variation and heterogeneity, with age-related changes and sex differences profoundly influencing phenotypic expression.[7]For instance, lipid levels typically increase with age, and women often present with different lipid profiles and CAD symptoms compared to men, contributing to a diverse spectrum of atypical presentations. This variability underscores the need for personalized assessment, considering an individual’s unique genetic background and environmental exposures that modulate the severity and progression of lipid dysregulation and cardiovascular disease.
From a diagnostic perspective, persistent abnormalities in lipid concentrations and an elevated risk of CAD serve as critical red flags, necessitating prompt clinical attention and intervention. [7]These findings hold significant diagnostic value, not only for identifying individuals at risk but also for guiding differential diagnoses against other metabolic or cardiovascular conditions. The presence of specific genetic markers influencing lipid levels and CAD risk, as identified in research, provides valuable prognostic indicators, allowing for earlier risk stratification and the implementation of targeted preventive strategies to improve long-term outcomes.[7]
Causes of Argininate
Section titled “Causes of Argininate”The levels and function of argininate, a metabolic trait potentially related to arginine metabolism and the activity of enzymes like arginine carboxypeptidase-1, are influenced by a complex interplay of genetic, environmental, and physiological factors. Research into complex metabolic traits, such as serum uric acid levels, provides a framework for understanding the multifaceted etiology of such biochemical characteristics.
Genetic Determinants and Metabolic Regulation
Section titled “Genetic Determinants and Metabolic Regulation”Genetic factors play a significant role in determining an individual’s argininate levels. A key gene directly implicated isCPN1, which encodes arginine carboxypeptidase-1, a metalloprotease primarily expressed in the liver and found in plasma. This enzyme is crucial for inactivating potent vasoactive and inflammatory peptides that contain C-terminal arginine or lysine, such as kinins and anaphylatoxins.[3] Therefore, inherited variations or defects in CPN1can directly impact the activity of arginine carboxypeptidase-1, potentially leading to altered argininate levels or related metabolic imbalances.[3]
Beyond single gene effects, argininate, like other complex metabolic traits, is likely influenced by a polygenic architecture. Studies on related metabolites, such as uric acid, reveal that multiple genes contribute to its regulation. For instance, common variants in genes likeSLC2A9 (also known as GLUT9), ABCG2, and SLC17A3have been strongly associated with serum uric acid levels, with an additive genetic risk score from these loci showing graded associations with the trait.[1] These genes often encode transporters or enzymes involved in kidney and liver metabolism, highlighting the conserved biological pathways that regulate circulating metabolite concentrations. For example, SLC2A9encodes a putative glucose transporter highly expressed in the kidney and liver, and its variants can significantly affect metabolite levels.[1] Similarly, ABCG2encodes a transporter in kidney proximal tubule cells that handles purine nucleoside analogues, reflecting its role in metabolic waste product management.[8]
Environmental Modulators and Lifestyle Influences
Section titled “Environmental Modulators and Lifestyle Influences”Environmental factors, including lifestyle and diet, are critical in shaping the expression of genetically predisposed metabolic traits. While specific dietary or lifestyle impacts on argininate are not detailed, insights from studies on related metabolic markers suggest that external factors can significantly modulate biochemical levels. Geographic location and socioeconomic conditions can also contribute to variations, potentially reflecting differences in typical diets, exposure to environmental agents, or access to healthcare, which collectively influence metabolic health across populations. For example, studies conducted in diverse populations such as Sardinians, Chianti cohorts, Old Order Amish, and individuals in Southern Germany and the U.S. highlight how population-specific genetic backgrounds and environmental contexts might interact to affect metabolic profiles.[1]
Interactions Between Genes and Environment
Section titled “Interactions Between Genes and Environment”The manifestation of argininate levels is not solely a product of an individual’s genetic makeup or environmental exposures in isolation, but rather a result of intricate gene-environment interactions. Genetic predispositions can be amplified or mitigated by specific environmental triggers. For instance, research on uric acid has demonstrated significant gene-by-sex interactions, where certain genetic variants, such asrs16890979 in SLC2A9 and rs2231142 in ABCG2, explain different proportions of variance in metabolite levels between men and women. [8]This indicates that the effect of a specific genetic variant on a metabolic trait can be modified by biological sex, an inherent environmental factor. Such interactions underscore the complexity of metabolic regulation, suggesting that personalized approaches considering both genetic background and lifestyle are crucial for understanding and managing conditions related to argininate.
Age-Related Changes and Comorbid Conditions
Section titled “Age-Related Changes and Comorbid Conditions”Beyond primary genetic and environmental influences, argininate levels can be further affected by an individual’s physiological state, including age and the presence of comorbid health conditions. Metabolic traits often show age-related trends; for instance, certain metabolite levels are known to generally increase with advancing age.[1]This suggests that the cumulative effects of aging on organ function, particularly in the liver and kidneys which are central to arginine metabolism and waste product handling, can alter argininate concentrations over a lifetime.[1]Furthermore, the presence of other health issues, or comorbidities, can indirectly influence argininate. Metabolic disorders are frequently correlated with conditions such as hypertension and cardiovascular disease, which can impact overall metabolic homeostasis and potentially affect the activity of enzymes like arginine carboxypeptidase-1 or the peptides it processes.[9]
Enzymatic Activity and Molecular Targets
Section titled “Enzymatic Activity and Molecular Targets”The CPN1gene encodes arginine carboxypeptidase-1, a crucial liver-expressed plasma metalloprotease that acts as a key biomolecule in the body’s proteolytic systems.[3]This enzyme specifically targets and cleaves C-terminal arginine residues from various peptides, representing a precise molecular and cellular pathway for modifying their biological activity.[3] This enzymatic action is fundamental for the controlled degradation and regulation of circulating factors that influence numerous physiological processes.
Systemic Effects and Homeostatic Regulation
Section titled “Systemic Effects and Homeostatic Regulation”The primary function of arginine carboxypeptidase-1 is to protect the body by inactivating potent vasoactive and inflammatory peptides, such as kinins and anaphylatoxins, which are released into the circulation.[3] By degrading these peptides, the enzyme exerts systemic consequences, modulating tissue interactions and maintaining overall homeostatic balance. This crucial action prevents the uncontrolled activity of molecules that could otherwise trigger widespread inflammatory responses or vascular changes throughout the body.
Genetic Control of Carboxypeptidase-1
Section titled “Genetic Control of Carboxypeptidase-1”The production and functional activity of arginine carboxypeptidase-1 are directly governed by theCPN1 gene. [3] This genetic mechanism dictates the synthesis of the enzyme, influencing its expression patterns and overall availability in the plasma. Regulatory elements associated with CPN1 ensure its appropriate liver-specific expression, highlighting the gene’s central role in the body’s protective systems and regulatory networks.
Pathophysiological Consequences of Dysfunction
Section titled “Pathophysiological Consequences of Dysfunction”Defects in CPN1 can lead to impaired carboxypeptidase activity, disrupting the body’s ability to properly process and inactivate critical peptides. [3]This homeostatic disruption can result in the accumulation of active vasoactive and inflammatory molecules, thereby contributing to various pathophysiological processes and disease mechanisms. The inability to properly regulate these peptides underscores the importance ofCPN1 in preventing chronic inflammation and vascular disorders.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Transport and Regulation of Urate
Section titled “Metabolic Transport and Regulation of Urate”The regulation of serum uric acid levels is primarily governed by metabolic transport mechanisms, prominently featuring the facilitative glucose transporter-like protein 9 (GLUT9), also known as SLC2A9. This protein acts as a crucial urate transporter, influencing both serum urate concentrations and its excretion, particularly in the kidney.[10]A highly conserved hydrophobic motif within the exofacial vestibule of fructose-transportingSLC2A proteins, including GLUT9, is a critical determinant of their substrate selectivity, highlighting the molecular basis for its transport function. [10] The identification of GLUT9as a key player in renal urate transport provides new insights into the control of blood urate levels, which are critical for maintaining metabolic balance.[11]
Beyond urate, the body employs other enzymatic mechanisms to regulate bioactive peptides. For instance,CPN1encodes arginine carboxypeptidase-1, a liver-expressed plasma metalloprotease. This enzyme plays a protective role by inactivating potent vasoactive and inflammatory peptides, such as kinins or anaphylatoxins, that contain C-terminal arginine or lysine residues, once they are released into the circulation.[3] This highlights distinct but equally vital metabolic regulatory pathways that manage diverse biomolecules within the body.
Genetic and Post-Translational Regulatory Mechanisms
Section titled “Genetic and Post-Translational Regulatory Mechanisms”Genetic variations, specifically single nucleotide polymorphisms (SNPs) within theGLUT9gene, have been consistently associated with serum uric acid levels, underscoring a significant genetic regulatory layer.[10] Beyond inherited genetic differences, post-translational regulatory mechanisms, such as alternative splicing, play a critical role in modulating protein function and cellular trafficking. Studies have shown that alternative splicing of human GLUT9alters its trafficking within cells, potentially leading to different functional isoforms that could impact urate transport efficiency.[12] Such intricate regulatory control ensures the precise expression and localization of transporters like GLUT9, adapting their activity to physiological demands.
Systems-Level Metabolic Integration
Section titled “Systems-Level Metabolic Integration”The regulation of serum uric acid is not an isolated process but is deeply integrated into broader physiological systems, demonstrating significant pathway crosstalk. Elevated uric acid levels are linked to the metabolic syndrome, a cluster of conditions that increase the risk of heart disease, stroke, and type 2 diabetes.[13]Furthermore, uric acid has been implicated in the pathogenesis of hypertension and progressive renal disease, suggesting its involvement in complex feedback loops that affect cardiovascular and kidney health.[14] The interplay between GLUT9-mediated urate transport and systemic metabolic health illustrates a hierarchical regulation where dysregulation in one pathway can have emergent properties affecting multiple physiological systems.
Disease-Relevant Mechanisms and Therapeutic Implications
Section titled “Disease-Relevant Mechanisms and Therapeutic Implications”Dysregulation of urate metabolism, often influenced by variants inGLUT9, is a primary mechanism underlying disease states such as hyperuricemia and gout.[15]Beyond its direct role in gout, uric acid’s pathogenetic contributions extend to cardiovascular and renal diseases, suggesting that managing uric acid levels could be a new paradigm in cardiovascular risk management.[14] Understanding these mechanisms and the specific roles of transporters like GLUT9provides potential therapeutic targets for interventions aimed at normalizing serum uric acid levels and mitigating associated health risks, including hypertension and broader cardiovascular complications.[14]
The provided research studies do not contain specific information regarding ‘argininate’. Therefore, a clinical relevance section for this trait cannot be generated from the given context.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs112201728 rs34130495 | SLC22A1 | urinary metabolite measurement N-acetylarginine measurement plasma betaine measurement acisoga measurement adipoylcarnitine (C6-DC) measurement |
| rs13107325 | SLC39A8 | body mass index diastolic blood pressure systolic blood pressure high density lipoprotein cholesterol measurement mean arterial pressure |
| rs3737704 | CELA2B | argininate measurement |
| rs10223601 rs73542824 | ARG1 | argininate measurement |
| rs113177297 | AGMAT, DNAJC16 | argininate measurement |
| rs80254170 | IGF2R | phospholipids in medium LDL measurement free cholesterol in medium LDL measurement total cholesterol in medium LDL free cholesterol in small VLDL measurement triglyceride measurement, high density lipoprotein cholesterol measurement |
| rs6667064 | DNAJC16 | argininate measurement |
| rs12582333 | GRIN2B | argininate measurement |
| rs137938669 | RNU6-633P - LINC01290 | argininate measurement |
| rs80169023 | SLC8A1-AS1 | argininate measurement |
References
Section titled “References”[1] Li, S., et al. “The GLUT9 Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts.”PLoS Genet, 2007.
[2] Wallace, Cathryn, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, 2008.
[3] Yuan, X. et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, 2008.
[4] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, 2008.
[5] Saxena, Richa, et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.” Science, vol. 316, no. 5829, 2007, pp. 1331-1336.
[6] Benjamin, E. J. et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, 2007.
[7] Willer, C. J. et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, 2008.
[8] Dehghan, A. et al. “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.”Lancet, 2008.
[9] Messerli, F. H., et al. “Serum uric acid in essential hypertension: an indicator of renal vascular involvement.”Ann Intern Med, 1980.
[10] McArdle, P. F., et al. “Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish.”Arthritis Rheum, 2008.
[11] Anzai, N., et al. “New insights into renal transport of urate.”Curr Opin Rheumatol, 2007.
[12] Augustin, R., et al. “Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.”J Biol Chem, 2004.
[13] Cirillo, P., et al. “Uric Acid, the metabolic syndrome, and renal disease.”J Am Soc Nephrol, 2006.
[14] Johnson, R. J., et al. “Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link?”J Am Soc Nephrol, 2005.
[15] Vitart, V., et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.”Nat Genet, 2008.