Arginine
Arginine is a semi-essential alpha-amino acid that plays a crucial role in numerous physiological processes within the human body. As a conditionally essential amino acid, the body can typically synthesize it, but under certain conditions, such as rapid growth, stress, or illness, dietary intake becomes necessary.
Biological Basis
Section titled “Biological Basis”Arginine is a key component in protein synthesis and is a precursor for several vital molecules. It is a substrate for nitric oxide synthase, an enzyme that produces nitric oxide (NO), a potent vasodilator essential for cardiovascular health. Arginine is also involved in the urea cycle, a metabolic pathway that detoxifies ammonia, and serves as a precursor for creatine, a compound important for energy production in muscles and nerves, and polyamines, which are involved in cell growth and differentiation. The levels of arginine and its related metabolites are tightly regulated, reflecting the complex interplay of genetic and environmental factors that contribute to an individual’s metabolic profile.
Clinical Relevance
Section titled “Clinical Relevance”Variations in arginine levels and its metabolites have been linked to a range of health conditions. Research suggests a possible role for arginine in various cardiometabolic and renal diseases, including diabetic retinopathy and cystic kidney disease.[1]Several arginine-related metabolites are also of significant clinical interest:
- Homoarginine:Genetically predicted plasma levels of homoarginine have been positively associated with an increased risk of chronic kidney disease (CKD).[1]This finding contrasts with some observational studies that linked higher homoarginine levels to lower renal and cardiometabolic disease risk, suggesting the need for careful monitoring of kidney function during homoarginine supplementation strategies.[1] Genetic variants associated with homoarginine levels are likely linked to transporters like SLC15A19 and SLC7A7.[1] - Asymmetric and Symmetric Dimethylarginine (ADMA and SDMA):These catabolites of arginine have been implicated in cardiometabolic disease, primarily due to their suggested vasodilatory roles. Some studies have even indicated a putative adverse effect of higher arginine on coronary artery disease (CAD).[2] - N-acetylarginine:Genetically high levels of N-acetylarginine have been observed to decrease levels of IGFBP-6, a protein with cancer-protective, immune system, and neuronal protection properties.[3] N-acetylarginine is a guanidino compound known to induce seizures in animal models, and high levels are characteristic of argininemia, a condition marked by neurological symptoms.[3]Common single nucleotide polymorphisms (SNPs) can explain a significant proportion of the variance in N-acetylarginine levels.[1] - Genetic associations: The HLA-Cgene has been found to be associated with arginine levels.[4]
Social Importance
Section titled “Social Importance”Understanding the genetic and environmental factors influencing arginine levels and its metabolic pathways is crucial for personalized medicine and public health. Genetic studies contribute to identifying individuals at higher risk for certain diseases and can inform targeted interventions. For instance, the complex relationship between homoarginine and CKD highlights the importance of genetic insights in guiding supplementation strategies. Furthermore, the links between arginine metabolites and conditions like neurological disorders underscore the broader impact on quality of life and the potential for early detection and management. Research into arginine and its metabolites helps to unravel the intricate mechanisms of metabolic individuality and its profound effects on human health.[1]
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Genetic studies of arginine levels face several methodological and statistical challenges that influence the interpretation and reproducibility of findings. Replication efforts, despite often showing consistent directions of effect for many associations, yield a modest number of statistically significant replications when stringent corrections are applied.[3] This discrepancy can be attributed to modest sample sizes in replication cohorts and potential heterogeneity across studies, which may reduce statistical power, particularly for detecting the effects of low-frequency variants.[3] Consequently, some initial discoveries may represent inflated effect sizes or lack robust evidence for consistent association across diverse study populations.
The analytical approaches, while designed to reduce Type I errors and improve power through methods like rank-normalization and adjustments for various covariates, can still be affected by the inherent complexity of metabolic traits.[3] For instance, the exclusion of outlier individuals or the choice to present results without adjusting for certain environmental factors like BMI, even if effects are generally similar, could subtly influence reported associations and their generalizability to the broader population.[5]These considerations highlight the ongoing need for larger, well-powered studies and harmonized analytical pipelines to solidify genetic associations with arginine and its related metabolites.
Ancestry and Generalizability
Section titled “Ancestry and Generalizability”A significant limitation in understanding the genetic architecture of arginine metabolism is the predominant focus on populations of European ancestry in many large-scale genomic studies.[6] While efforts are being made to include multi-ethnic cohorts, the sample sizes for non-European groups, such as African, Hispanic, South Asian, and East Asian individuals, are frequently insufficient to provide adequate statistical power for comprehensive analyses.[3]This ancestral imbalance restricts the generalizability of findings to diverse global populations and may lead to an incomplete understanding of how genetic variants influence arginine levels across different genetic backgrounds.
Even when associations show consistent directions of effect across multiple ancestries, the statistical significance can vary considerably, with some findings remaining non-significant in smaller, non-European cohorts due to insufficient power.[3] This underscores the need for substantial increases in sample sizes for underrepresented populations to fully elucidate ancestry-specific genetic effects and to ensure that the benefits of genomic research are equitably distributed. Without such diversity, the full spectrum of genetic determinants and their clinical relevance may remain obscured.
Phenotypic Complexity and Environmental Influences
Section titled “Phenotypic Complexity and Environmental Influences”The accurate and specific characterization of arginine and its related metabolites presents inherent challenges that impact genetic association studies. Metabolomics platforms may struggle to differentiate between structurally similar compounds, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), potentially confounding the identification of specific genetic drivers for each metabolite.[1] Furthermore, variability in metabolite characterization procedures, the influence of batch effects, and the impact of sample handling and storage conditions across different studies can introduce technical noise, necessitating extensive data processing and normalization that may not fully eliminate all biases.[3]Beyond characterization, the levels of arginine and its derivatives are profoundly influenced by a complex interplay of genetic, environmental, and lifestyle factors. Although studies typically adjust for key covariates such as age, sex, and time since last meal, residual confounding from unmeasured environmental exposures or gene-environment interactions cannot be entirely ruled out.[7] Additionally, the precise functional annotation of associated genetic variants based solely on physical distance to adjacent genes is often imprecise, and the field still lacks a fully curated and comprehensive catalog of genetic associations with molecular phenotypes, contributing to remaining knowledge gaps and the challenge of translating genetic findings into biological mechanisms.[6]
Variants
Section titled “Variants”Genetic variations play a crucial role in shaping an individual’s arginine levels and related metabolic pathways. Several genes are implicated in the synthesis, transport, and catabolism of arginine, with specific variants influencing these processes and potentially impacting overall health. Arginine is an essential amino acid involved in diverse physiological functions, including nitric oxide production, immune response, and the urea cycle, which is vital for detoxifying ammonia.[1]Abnormal circulating amino acid levels are a recognized phenotype associated with genetic variations impacting metabolic pathways.[8]Key variants in genes central to arginine metabolism include those within_ARG1_, _CPS1_, and _SLC7A2_. The _ARG1_gene encodes arginase 1, an enzyme that converts arginine into ornithine and urea, representing a critical step in the urea cycle. Variants such asrs17788484 and rs74451798 in _ARG1_may alter the efficiency of this conversion, thereby affecting plasma arginine concentrations. Similarly,_CPS1_(Carbamoyl Phosphate Synthetase 1) is the rate-limiting enzyme in the urea cycle, catalyzing the first step of ammonia detoxification. Variations likers715 and rs1047891 in _CPS1_can impact the overall capacity of the urea cycle, indirectly influencing arginine availability and contributing to abnormal amino acid levels.[8] The _SLC7A2_gene, encoding a cationic amino acid transporter, is directly involved in the cellular uptake and efflux of arginine, lysine, and ornithine. The intronic variantrs56335308 in _SLC7A2_is associated with plasma glycogen levels and is implicated in arginine metabolism, with studies showing that_Slc7a2_knockout mice exhibit higher blood glucose, highlighting its broad metabolic relevance.[4]Other genetic variations impact broader amino acid catabolism and gene regulation, indirectly affecting arginine homeostasis. Variantsrs56397034 and rs3817621 are found within _GCDH_(Glutaryl-CoA Dehydrogenase), an enzyme critical for the catabolism of lysine, hydroxylysine, and tryptophan. Disruptions in these pathways, such as those caused by_GCDH_deficiency, can lead to accumulation of other amino acid metabolites, potentially perturbing the overall amino acid pool and impacting arginine’s metabolic fate. The_MED23_ gene, which encodes a subunit of the Mediator complex, plays a vital role in regulating gene expression. Variants like rs2246012 and rs2781668 in _MED23_could influence the transcription of numerous genes, including those involved in metabolic pathways, thereby having widespread effects on cellular metabolism and potentially altering arginine levels through indirect mechanisms.
Beyond direct metabolic enzymes and transporters, several genes and their variants exert more indirect or pleiotropic effects on arginine and related metabolic traits._KLF1_ (Kruppel-like factor 1) is a transcription factor primarily known for erythroid development, but its broader regulatory roles may influence metabolic processes. _PYROXD2_(Pyridoxamine 5’-phosphate Oxidase-like 2) variants, includingrs11189591 , rs2182168 , and rs10883083 , could be relevant due to the role of pyridoxamine 5’-phosphate oxidase in vitamin B6 metabolism, a cofactor for many amino acid-metabolizing enzymes. Similarly,_HPS1_ (Hermansky-Pudlak Syndrome 1), involved in lysosome-related organelle biogenesis, may contribute to systemic metabolic changes through its role in cellular trafficking and function, with variant rs1737 potentially having implications. Pseudogenes like _GUSBP5_ (variant rs6814613 ) and _ATP5PBP6_ (variant rs628751 ), along with long non-coding RNAs such as _LINC01625_, can exert regulatory influences on gene expression, thereby indirectly affecting metabolic pathways and potentially contributing to variations in arginine levels or related metabolic profiles.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs17788484 | ARG1 | arginase-1 ornithine arginine metabolite serum metabolite level |
| rs56397034 rs3817621 | KLF1 - GCDH | erythrocyte volume erythrocyte count mean corpuscular hemoglobin arginine mean corpuscular hemoglobin concentration |
| rs74451798 | MED23, ARG1 | arginine |
| rs11189591 rs2182168 rs10883083 | PYROXD2 | arginine metabolite N6,N6-dimethyllysine N6-methyllysine |
| rs1737 | HPS1 | arginine |
| rs2246012 rs2781668 | ARG1, MED23 | body mass index cerebral cortex area attribute ARG1/PKLR protein level ratio in blood ARG1/HAGH protein level ratio in blood ARG1/HMBS protein level ratio in blood |
| rs6814613 | GUSBP5 | arginine |
| rs715 rs1047891 | CPS1 | circulating fibrinogen levels plasma betaine eosinophil percentage of leukocytes platelet crit macular telangiectasia type 2 |
| rs56335308 | SLC7A2 | L-arginine , amino acid ornithine , amino acid arginine L-arginine alanine |
| rs628751 | LINC01625 - ATP5PBP6 | mean corpuscular hemoglobin erythrocyte volume ARG1/HAGH protein level ratio in blood arginine mean corpuscular hemoglobin concentration |
Arginine: Definition, Physiological Roles, and Associated Conditions
Section titled “Arginine: Definition, Physiological Roles, and Associated Conditions”Arginine is a semi-essential amino acid, crucial for numerous physiological processes, including nitric oxide synthesis, protein metabolism, and immune function. Its levels in plasma are routinely measured as a key metabolite, providing insights into an individual’s metabolic individuality and health status.[1]Deviations in arginine levels are associated with a range of clinical conditions, highlighting its significance as a potential biomarker. For instance, observational epidemiology describes associations between arginine levels and Type 2 Diabetes (T2D).[7]and research indicates a possible role in cardiometabolic and renal diseases, such as diabetic retinopathy and cystic kidney disease.[1]The term “arginine-related metabolites” encompasses not only arginine itself but also related compounds like homoarginine, and (a)symmetric dimethylarginine (ADMA and SDMA), which are also under investigation for their roles in disease pathology.[1]
Approaches and Analytical Frameworks
Section titled “Approaches and Analytical Frameworks”The of arginine and its related metabolites in biological systems typically employs advanced analytical techniques such as untargeted metabolomic profiling, often utilizing ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry (LC-HRMS).[3]Operational definitions for arginine levels are commonly expressed as plasma concentrations, which are then analyzed in large-scale genomic studies. In genetic association studies, quantitative measurements often undergo processes like inverse normalization of residuals to ensure statistical robustness.[5]To accurately interpret genetic influences on arginine levels, analytical terminology includes concepts like “BMI adjustment,” where body mass index is included as a covariate to account for its known influence on metabolite levels.[5] and “genomic inflation factor,” which assesses the calibration of GWAS p-values.[7]Furthermore, “colocalization methods” are used to determine if genetic determinants of arginine share a single causal signal with disease outcomes.[7]
Classification of Arginine-Related Disorders and Biomarkers
Section titled “Classification of Arginine-Related Disorders and Biomarkers”Within broader nosological systems, conditions related to abnormal arginine metabolism can fall under classifications such as “Abnormal circulating amino acid level” or “Abnormal amino acid level”.[8]Specific diagnostic criteria for arginine-related disorders often involve assessing plasma concentrations, as seen in conditions like hyperargininemia, characterized by increased arginine levels and associated neurological dysfunctions.[3]While precise clinical thresholds or cut-off values for arginine itself are context-dependent and evolve with research, its association with diseases like T2D and cardiometabolic conditions suggests its utility as a diagnostic and prognostic biomarker.[7]Related metabolites such as homoarginine, ADMA, and SDMA are also recognized for their distinct roles; for instance, homoarginine levels are linked to chronic kidney disease (CKD) risk, with genetic variants nearGATM and transporters like SLC15A19 and SLC7A7 influencing its plasma concentrations.[1]
Arginine Metabolism and Key Metabolites
Section titled “Arginine Metabolism and Key Metabolites”Arginine is a conditionally essential amino acid that plays a central role in numerous molecular and cellular pathways within the human body. It serves as a precursor for various critical biomolecules, including nitric oxide, creatine, and polyamines, highlighting its diverse metabolic functions.[2]The metabolism of arginine generates several important derivatives, such as homoarginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-acetylarginine, each with distinct physiological roles and implications for health. These metabolites are integral to regulatory networks governing cardiovascular function, renal health, and neurological processes, making the precise regulation of arginine levels crucial for maintaining homeostasis.[2]Homoarginine, a structural analog of arginine, is transported by specific proteins likeSLC15A19 and SLC7A7, indicating dedicated cellular uptake and distribution mechanisms.[1] ADMA and SDMA are closely related metabolites known for their suggested vasodilatory roles, influencing vascular tone and blood flow.[2] N-acetylarginine is a guanidino compound, a class of molecules that can profoundly impact the nervous system, with high levels potentially leading to neurological symptoms.[3]The balance and interconversion of these arginine metabolites are tightly regulated, reflecting their significant impact on cellular functions and overall metabolic individuality.
Genetic Influences on Arginine Homeostasis
Section titled “Genetic Influences on Arginine Homeostasis”The levels of arginine and its metabolites in the plasma are significantly influenced by an individual’s genetic makeup, with specific genetic mechanisms dictating their production, transport, and breakdown. Genetic variants in several genes have been associated with plasma arginine levels, including intronic variants within theAPBB2 and CHAF1A genes, as well as the HLA-C gene.[4]These genetic associations underscore the complex regulatory networks that govern arginine availability and utilization within cells and tissues.
Furthermore, the genetic determinants of arginine-related metabolites also reveal key insights into their biology. For instance, genetic variants linked to homoarginine levels are associated with the transportersSLC15A19 and SLC7A7, which specifically bind and move homoarginine across cell membranes.[1] A prominent intergenic variant, rs1145091 , located near the GATM gene, has been identified as a strong determinant of plasma homoarginine levels, suggesting that genetic variations near genes involved in guanidino compound synthesis or metabolism can have a significant impact . The efficiency and flux of this pathway are directly influenced by the activity of ARG1, and genetic determinants impacting this enzyme can significantly alter plasma arginine levels. Beyond its role in nitrogen disposal, arginine serves as a precursor for vital molecules such as nitric oxide, creatine, and polyamines, highlighting its broad involvement in energy metabolism, cardiovascular function, and cellular growth.
The regulation of arginine homeostasis is multifaceted, involving intricate genetic controls that modulate its availability and utilization. Studies have identified that intronic variants in genes likeAPBB2 and CHAF1Aare significantly associated with plasma arginine concentrations, indicating a role for these genetic loci in arginine metabolism.[4] Furthermore, the HLA-Cgene has also been linked to arginine levels, suggesting a complex interplay of genetic factors that influence the expression or activity of proteins involved in arginine biosynthesis, transport, or breakdown.[4]These regulatory mechanisms ensure that arginine levels are maintained within a physiological range, critical for supporting its diverse metabolic functions.
Genetic Determinants of Arginine Homeostasis
Section titled “Genetic Determinants of Arginine Homeostasis”Individual variability in plasma arginine and its related metabolites is substantially shaped by genetic factors. Genome-wide association studies have pinpointed several genetic loci that influence circulating arginine levels, including specific variants within or adjacent to genes such asAPBB2, CHAF1A, and HLA-C.[4]These genetic associations imply that variations in the regulatory regions or coding sequences of these genes can impact the production, degradation, or transport of arginine, thereby contributing to an individual’s unique metabolic profile. This genetic architecture underlines the inherent complexity in maintaining arginine balance.
The levels of homoarginine, an arginine analogue, are also under strong genetic influence, with specific genetic variants linked to transporters such asSLC15A19 and SLC7A7.[1]These transporters are thought to mediate the specific uptake and efflux of homoarginine, distinguishing its metabolic handling from that of arginine. Notably, the intergenic variantrs1145091 , located near the GATMgene, has been identified as a significant genetic determinant for plasma homoarginine levels and is associated with chronic kidney disease.[1]These findings highlight how genetic variations can precisely control the concentrations of arginine and its derivatives, influencing their physiological roles.
Arginine-Related Metabolites and Systemic Integration
Section titled “Arginine-Related Metabolites and Systemic Integration”Arginine metabolism is intricately connected to a network of related compounds, each playing distinct roles in systemic health. Homoarginine, for instance, exhibits a unique physiological profile, with genetic evidence suggesting a role in chronic kidney disease pathology that is distinct from other arginine-related metabolites.[1] Its specific transport mechanisms, mediated by proteins like SLC15A19 and SLC7A7, further emphasize its independent metabolic fate and its contribution to broader physiological processes.[1]Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) represent another class of arginine catabolites, recognized for their suggested vasodilatory roles and potential to inhibit nitric oxide synthase.[1]The intricate interplay between arginine, homoarginine, ADMA/SDMA, and compounds like N-acetylarginine illustrates extensive pathway crosstalk and network interactions within the human metabolome. Changes in the levels of one metabolite, such as genetically high N-acetylarginine, can influence the concentrations of other metabolites, demonstrating a hierarchical regulation where metabolic shifts can have cascading effects across the network.[3]The modular nature of gene-metabolite networks further reveals the complex and integrated genetic contributions that give rise to emergent properties in health and disease.[4]
Disease Relevance and Therapeutic Implications
Section titled “Disease Relevance and Therapeutic Implications”Dysregulation within arginine metabolism and its associated pathways is profoundly implicated in various human diseases, presenting critical targets for therapeutic interventions. Hyperargininemia, a genetic disorder characterized by elevated arginine levels due to defects inArginase 1, results in severe neurological dysfunctions, underscoring the vital role of proper arginine catabolism for brain health.[9]Similarly, deficiencies in carbamoyl phosphate synthetase 1 (CPS1), another key enzyme in the urea cycle, severely impair nitrogen detoxification, leading to significant metabolic imbalances.[10]Furthermore, arginine and its metabolites are linked to kidney and cardiovascular diseases. Studies indicate a positive association between genetically predicted plasma homoarginine levels and the risk of chronic kidney disease.[1]This contrasts with some observational studies that suggested higher homoarginine levels were protective against renal and cardiometabolic disease, highlighting the complexity of its role and the need for careful monitoring during potential supplementation strategies.[11]This intricate relationship, alongside evidence suggesting a potential adverse effect of elevated arginine on coronary artery disease, positions these metabolic pathways as crucial areas for understanding disease pathophysiology and developing targeted therapies.[1]
Cardiovascular and Renal Disease Risk Stratification
Section titled “Cardiovascular and Renal Disease Risk Stratification”Arginine and its related metabolites, such as homoarginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), play a complex role in cardiovascular and renal health, offering potential as biomarkers for risk assessment and prognosis. Plasma levels of ADMA and SDMA have garnered significant attention due to their suggested vasodilatory roles and their association with overall mortality and cardiovascular outcomes.[2]While some studies suggest a putative adverse effect of higher arginine on coronary artery disease (CAD).[12]its direct involvement in cardiometabolic and renal diseases like diabetic retinopathy or cystic kidney disease shows only weak evidence.[1]These metabolites, therefore, represent targets for monitoring strategies and could aid in identifying high-risk individuals for cardiovascular and kidney complications.
Conversely, the clinical relevance of homoarginine is nuanced, presenting conflicting evidence regarding its prognostic value in renal and cardiovascular disease. While some observational studies have linked higher homoarginine levels with a lower risk of renal and cardiometabolic diseases.[11]recent genetic studies present a contrasting view. For instance, a positive association has been identified between genetically predicted plasma homoarginine levels and an increased risk of chronic kidney disease (CKD).[1] This discrepancy highlights the importance of closely monitoring kidney function if homoarginine supplementation strategies are considered, as potential adverse effects exist.[1]Further research into these divergent findings is crucial for clarifying homoarginine’s precise role in disease progression and informing personalized medicine approaches.
Metabolic and Neurological Implications
Section titled “Metabolic and Neurological Implications”Beyond cardiovascular and renal systems, arginine and its derivatives are implicated in a range of metabolic and neurological conditions, affecting diagnostic utility and long-term patient care. Genetically determined arginine levels and ratios, such as arginine/citrulline and arginine/phosphate, have been shown to colocalize with body mass index (BMI), CAD, and ischemic stroke, indicating a broader metabolic relevance.[7]Furthermore, the metabolite N-acetylarginine is of particular interest due to its associations with neurological health and cancer-protective properties. Genetically high levels of N-acetylarginine are linked to decreased levels ofIGFBP-6, a protein involved in immune function, neuronal protection, and cancer prevention.[3] High levels of N-acetylarginine are notably present in argininemia, a condition characterized by significant neurological symptoms, including seizures, as N-acetylarginine itself is a guanidino compound capable of inducing seizures in animal models.[3]Therefore, monitoring N-acetylarginine levels could serve as a diagnostic marker or a tool for assessing disease progression and treatment response in such neurological disorders. Understanding these metabolic and neurological associations allows for improved risk assessment, especially in syndromic presentations or overlapping phenotypes, paving the way for targeted interventions and prevention strategies.
Genetic Determinants and Personalized Medicine
Section titled “Genetic Determinants and Personalized Medicine”Genetic factors significantly influence individual arginine levels and the metabolism of its related compounds, offering insights into personalized medicine and risk stratification. For example, theHLA-Cgene has been specifically associated with plasma arginine levels.[4] Moreover, genetic variants linked to homoarginine levels are likely tied to transporters with specific affinities, such as SLC15A1 and SLC7A7.[1] The intergenic variant rs1145091 , located near the GATMgene, has been identified as the strongest genetic determinant for plasma homoarginine levels, suggesting a distinct pathological role for homoarginine in CKD compared to other arginine-related metabolites.[1]These genetic insights are crucial for identifying high-risk individuals and developing personalized prevention strategies. By understanding an individual’s genetic predisposition to altered arginine metabolism, clinicians may be able to tailor monitoring strategies, dietary recommendations, or potential therapeutic interventions. Such precision medicine approaches could improve prognostic predictions, guide treatment selection, and potentially mitigate long-term complications associated with dysregulated arginine pathways.
Frequently Asked Questions About Arginine
Section titled “Frequently Asked Questions About Arginine”These questions address the most important and specific aspects of arginine based on current genetic research.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Surendran P et al. “Rare and common genetic determinants of metabolic individuality and their effects on human health.” Nat Med., vol. 28, no. 11, 2022, pp. 2321–2332.
[2] Popolo, A. et al. “l-Arginine and its metabolites in kidney and cardiovascular disease.”Amino Acids, vol. 46, no. 10, 2014, pp. 2221–2230.
[3] Feofanova EV et al. “Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations.” Nat Commun., vol. 14, no. 1, 2023, p. 3100.
[4] Lee IH et al. “Comprehensive characterization of putative genetic influences on plasma metabolome in a pediatric cohort.” Hum Genomics., vol. 16, no. 1, 2022, p. 67.
[5] Yin, X. et al. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci.Nat Commun, 2022.
[6] Hysi, P. G., et al. “Metabolome Genome-Wide Association Study Identifies 74 Novel Genomic Regions Influencing Plasma Metabolites Levels.” Metabolites, vol. 12, no. 1, 2022, p. 84.
[7] Chen, Y. et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet, 2023.
[8] Schlosser, P et al. “Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine.” Nat Genet, 2023.
[9] Almeida, A. E., P., M. M., Dal, M. D., & de, L. D. The main neurological dysfunctions in hyperargininemia-literature review. Int. J. Neurol. Neurother., vol. 5, 2018, p. 074.
[10] Díez-Fernández, C., Gallego, J., Häberle, J., Cervera, J., & Rubio, V. The study of carbamoyl phosphate synthetase 1 deficiency sheds light on the mechanism for switching On/Off the urea cycle. J. Genet. Genomics, 2015.
[11] Pilz, S. et al. “Homoarginine in the renal and cardiovascular systems.”Amino Acids, vol. 47, no. 9, 2015, pp. 1757–1768.
[12] Au Yeung, S. L. et al. Effect of l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine on ischemic heart disease risk: a Mendelian randomization study.Am. Heart J., 2016.