Orotidine
Orotidine is a pyrimidine nucleoside, an essential intermediate in thede novobiosynthesis pathway of uridine monophosphate (UMP). This pathway is critical for generating pyrimidine nucleotides, which are fundamental building blocks for DNA and RNA synthesis, as well as components of various coenzymes and signaling molecules.
Biological Basis
Section titled “Biological Basis”In humans, orotidine is formed from orotate through the enzymatic action of orotate phosphoribosyltransferase (OPRT). Subsequently, orotidine is converted to UMP by orotidine 5’-phosphate decarboxylase (OMPDC). These two catalytic activities are often combined within a single bifunctional enzyme, uridine monophosphate synthase (UMPS). The efficient functioning of this pathway ensures a steady supply of pyrimidine nucleotides necessary for cell proliferation, repair, and overall metabolic homeostasis.
Clinical Relevance
Section titled “Clinical Relevance”Disruptions in orotidine metabolism can have significant health implications. For instance, deficiencies in theUMPSenzyme lead to a rare inherited metabolic disorder known as hereditary orotic aciduria, characterized by the accumulation of orotic acid and orotidine in bodily fluids, often resulting in megaloblastic anemia, developmental delay, and immunodeficiency. Beyond rare genetic disorders, modern metabolomics research investigates a broader spectrum of conditions. Studies focused on comprehensive metabolite profiling in human serum aim to identify how genetic variants influence the homeostasis of various biological molecules.[1]Such research explores associations between metabolite levels and complex traits, including lipid levels and coronary heart disease risk[2]as well as serum uric acid levels, which are implicated in conditions like gout and cardiovascular disease.[3]While the specific role of orotidine in these common conditions is still an active area of investigation, its position in a fundamental metabolic pathway suggests it could be a valuable indicator or target in future research.
Social Importance
Section titled “Social Importance”The study of metabolites like orotidine holds considerable social importance by contributing to a deeper understanding of human metabolism and disease mechanisms. By elucidating how genetic factors influence metabolite levels, researchers can identify potential biomarkers for early disease detection, stratify individuals for personalized medicine approaches, and uncover novel therapeutic targets. For example, understanding the genetic determinants of metabolite profiles allows for the investigation of pathways linked to complex diseases such as dyslipidemia and cardiovascular conditions, ultimately aiding in the development of more effective prevention and treatment strategies.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The studies on orotidine, like many genome-wide association studies (GWAS) of the era, were often constrained by moderate sample sizes, which limited their statistical power to detect genetic effects of modest magnitude.[4]This limitation means that genuine genetic associations contributing to orotidine levels might have been overlooked, leading to an increased likelihood of false negative findings. The necessity for stringent statistical thresholds to correct for the extensive multiple testing inherent in GWAS further reduced the ability to identify subtle but potentially important genetic influences.[4]Furthermore, the exclusion of single nucleotide polymorphisms (SNPs) with lower imputation quality (e.g., RSQR < 0.3) from meta-analyses, while enhancing data reliability, may have inadvertently excluded other relevant genetic variants.[5]
Another significant methodological concern stems from the incomplete genetic coverage, as the GWAS platforms used only a subset of all known SNPs, potentially missing genes that influence orotidine levels due to gaps in the genetic map.[6] In studies involving related individuals, inadequate modeling of polygenic effects or familial relatedness could lead to inflated p-values and an increased false-positive rate, even though some research attempted to account for this. [7]The choice to perform only sex-pooled analyses, rather than sex-specific analyses, might have masked certain genetic associations that are unique to males or females, thereby providing an incomplete picture of the genetic architecture underlying orotidine levels.[6]
Phenotype Assessment and Generalizability
Section titled “Phenotype Assessment and Generalizability”The method of phenotyping in some studies, particularly the averaging of measurements taken over extended periods—sometimes spanning decades and involving different equipment—introduces potential for misclassification. [4]This approach assumes that the genetic and environmental factors influencing orotidine levels remain constant across wide age ranges, an assumption that may not hold true and could obscure age-dependent genetic effects.[4] Such averaging strategies, while intended to characterize the phenotype better, could inadvertently dilute genuine associations or introduce bias if the underlying biological processes vary significantly over time.
A critical limitation for the generalizability of findings concerning orotidine is the predominant recruitment of cohorts consisting of individuals of white European ancestry.[8] While some studies implemented careful measures to address population stratification within these homogenous groups [9] the direct applicability of these results to other ethnic populations remains largely unknown. Genetic variants and their effect sizes can vary considerably across different ancestral groups due to differences in allele frequencies, linkage disequilibrium patterns, and diverse environmental exposures, thereby limiting the universal relevance of associations discovered in ethnically restricted cohorts. [4]
Unaccounted Environmental Factors and Knowledge Gaps
Section titled “Unaccounted Environmental Factors and Knowledge Gaps”A notable omission in many studies is the investigation of gene-environment interactions, which are fundamental to understanding complex traits like orotidine levels.[4]Genetic variants often exert their influence in a context-specific manner, with their effects being modulated by various environmental factors such as dietary intake or lifestyle. The absence of such analyses means that crucial interactions, where genetic predispositions are either enhanced or suppressed by environmental conditions, were not identified, leading to a potentially oversimplified view of the genetic underpinnings of orotidine levels.[4]
Furthermore, despite the identification of multiple genetic loci, there remain significant knowledge gaps regarding the comprehensive genetic architecture of orotidine. The ultimate validation of reported findings necessitates replication in independent cohorts and thorough functional characterization of the associated genetic variants.[10] It is acknowledged that some associations, particularly those with modest statistical support, could represent false-positive findings, highlighting the critical need for independent confirmation. [4]The total phenotypic variation explained by the discovered genetic variants often accounts for only a fraction of the estimated heritability, suggesting that a substantial portion of the genetic contribution to orotidine levels, potentially including rare variants or more complex genetic interactions, remains undiscovered.
Variants
Section titled “Variants”SLC2A9 (also known as GLUT9) is a crucial transporter protein belonging to the facilitated hexose transporter family, primarily responsible for the regulation of serum uric acid levels.[11]This gene codes for a 540 amino acid protein expressed predominantly in the liver, kidney, and placenta, with a splice variant, GLUT9ΔN, specifically found in kidney proximal tubule epithelial cells, the main site for renal uric acid regulation.[12] Variants like rs13125209 within SLC2A9can influence how efficiently uric acid is transported, impacting its concentration in the blood and excretion, and are strongly associated with conditions like gout.[3]While directly involved in urate transport, changes in urate metabolism, an end-product of purine degradation, can reflect broader metabolic imbalances that may indirectly influence orotidine pathways, given the interconnectedness of nucleotide biosynthesis and degradation.
The UMPSgene encodes UMP synthase, a bifunctional enzyme essential for the de novo pyrimidine biosynthesis pathway, converting orotate to orotidine monophosphate (OMP) and then OMP to uridine monophosphate (UMP). Variants inUMPS, along with those in the adjacent ITGB5 gene, such as rs2055983 and rs557189622 , could potentially impair this critical step, leading to an accumulation of orotidine and its precursor orotate, which is characteristic of orotic aciduria.NT5C(cytosolic 5’-nucleotidase) plays a role in nucleotide metabolism by dephosphorylating nucleoside monophosphates, converting them into nucleosides that can be salvaged or excreted. A variant such asrs11541956 in NT5Cmight alter the balance of nucleoside pools, indirectly affecting the availability of substrates or the removal of products in pyrimidine synthesis, thus potentially influencing orotidine levels. Another significant gene,ABCG2(ATP-binding cassette subfamily G member 2), functions as a high-capacity urate transporter, primarily involved in the excretion of uric acid.[11] The variant rs2231142 in ABCG2is a well-known polymorphism that can reduce its transport activity, leading to higher serum uric acid levels and an increased risk of gout, reflecting an overlapping metabolic trait with aspects of nucleotide metabolism.
Several other genes and their variants contribute to diverse cellular functions that, while not directly linked to orotidine in current research, are part of the broader metabolic and regulatory landscape as explored in genome-wide association studies.[6] JPT1 (Jupiter Microtubule Associated Protein 1) is involved in cytoskeletal organization and transport within cells, and variants like rs77950538 , rs141237548 , and rs78625720 could potentially affect cellular trafficking of metabolic enzymes or substrates. NUP85 encodes a component of the nuclear pore complex, essential for nucleocytoplasmic transport, and a variant such as rs78800630 might subtly influence the movement of nucleotides or regulatory molecules into or out of the nucleus, potentially impacting gene expression related to metabolic pathways. RASAL2 (RAS Protein Activator Like 2) acts as a GTPase-activating protein for RAS, a key signaling molecule, and rs569990662 might modulate cell signaling pathways that regulate growth and metabolism. The long intergenic non-coding RNA LINC02356, with its variant *rs10774624 _, and RBFOX1 (RNA Binding Fox-1 Homolog 1), with rs546243495 , are involved in gene regulation and RNA splicing, respectively; alterations here could broadly impact the expression of metabolic enzymes or transporters, as often revealed in comprehensive genetic analyses. [8] Lastly, the region encompassing POLR2DP2 (RNA Polymerase II Subunit D Pseudogene 2) and SNORA25B (Small Nucleolar RNA, H/ACA Box 25B), harboring variant rs777824167 , could play a role in RNA processing or transcriptional regulation, indirectly influencing the cellular capacity for pyrimidine synthesis or other metabolic processes.
The provided research material does not contain information about ‘orotidine’. Therefore, a Classification, Definition, and Terminology section cannot be generated based on the given context.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs77950538 rs141237548 rs78625720 | JPT1 | orotidine measurement |
| rs2055983 rs557189622 | UMPS - ITGB5 | orotidine measurement cerebrospinal fluid composition attribute, orotate measurement orotate measurement |
| rs11541956 | NT5C | protein measurement orotidine measurement |
| rs78800630 | NUP85 | orotidine measurement |
| rs569990662 | RASAL2 | orotidine measurement |
| rs2231142 | ABCG2 | urate measurement uric acid measurement trait in response to allopurinol, uric acid measurement gout gout, hyperuricemia |
| rs10774624 | LINC02356 | rheumatoid arthritis monokine induced by gamma interferon measurement C-X-C motif chemokine 10 measurement Vitiligo systolic blood pressure |
| rs546243495 | RBFOX1 | orotidine measurement |
| rs777824167 | POLR2DP2 - SNORA25B | orotidine measurement |
| rs13125209 | SLC2A9 | orotidine measurement |
Metabolic Pathways and Homeostatic Control
Section titled “Metabolic Pathways and Homeostatic Control”Genetic variations play a crucial role in regulating various metabolic processes and maintaining physiological homeostasis. In lipid metabolism, genetic variants in genes such as MLXIPLhave been associated with plasma triglyceride levels[13] suggesting its involvement in the synthesis or breakdown of fats. Similarly, a null mutation in human APOC3 has been shown to confer a favorable plasma lipid profile and offer apparent cardioprotection [14]underscoring the importance of this apolipoprotein in lipid transport and cardiovascular health. Furthermore, common single nucleotide polymorphisms (SNPs) inHMGCR, a key enzyme in cholesterol synthesis, are linked to LDL-cholesterol levels and influence the alternative splicing of its exon13. [15]These findings, along with others identifying loci for high-density lipoprotein cholesterol[1] and polygenic dyslipidemia [16] collectively highlight the intricate genetic architecture underlying lipid profiles.
Beyond lipids, other vital metabolic pathways are under genetic influence. The SLC2A9 gene, also known as GLUT9, is a newly identified urate transporter that significantly influences serum uric acid concentrations and urate excretion.[3] Variants in SLC2A9are strongly associated with gout and exhibit pronounced sex-specific effects on uric acid levels.[17]Uric acid itself is recognized as an important antioxidant in humans.[3] In iron homeostasis, genetic variations in TF(transferrin) andHFE(hemochromatosis protein) are substantial contributors, explaining approximately 40% of the genetic variation observed in serum-transferrin levels[18] illustrating their critical roles in systemic iron transport and regulation.
Cellular Functions and Coagulation Pathways
Section titled “Cellular Functions and Coagulation Pathways”Cellular functions, particularly those involved in hemostasis, are subject to genetic modulation. Platelet aggregation, a fundamental process for preventing bleeding and forming blood clots, is a complex trait influenced by genetic variants affecting its response to different stimuli. Studies have identified genetic associations with ADP-induced, collagen-induced, and epinephrine-induced platelet aggregation. [6] Among the genes implicated are several olfactory receptors, specifically OR5AP2, OR5AR1, OR9G1, and OR9G4, which are associated with platelet aggregation phenotypes. [6] Additionally, the DPYD gene, encoding dihydropyrimidine dehydrogenase, has also been linked to ADP-induced platelet aggregation. [6] These findings suggest diverse molecular pathways, potentially including novel signaling cascades involving olfactory receptors, contribute to the intricate regulatory networks governing platelet activity and overall hemostatic balance.
Genetic Modulators of Physiological Traits
Section titled “Genetic Modulators of Physiological Traits”Genome-wide association studies (GWAS) have advanced the understanding of how genetic variations, predominantly single nucleotide polymorphisms (SNPs), modulate a wide array of physiological traits. These studies provide insights into gene functions and regulatory networks that govern metabolic and cellular processes. For example, specific genetic variants are identified to influence parameters such as plasma triglycerides[13]serum uric acid levels[3] and various aspects of platelet aggregation. [6] The impact of genetic mechanisms extends to post-transcriptional regulation, as evidenced by common SNPs in the HMGCR gene affecting the alternative splicing of exon13, which subsequently influences LDL-cholesterol levels. [15] Such regulatory elements underscore the multifaceted ways genetic information is expressed and modified to affect physiological outcomes.
The emerging field of metabolomics, which involves the comprehensive measurement of endogenous metabolites, is being integrated with genetic research to provide a functional readout of the physiological state. [1]Genetic variants that associate with changes in the homeostasis of key metabolites like uric acid, as seen withSLC2A9, highlight the power of this approach in identifying genetic determinants of metabolic phenotypes. [1]These genetic-metabolomic links offer a deeper understanding of the molecular basis of health and disease, demonstrating how specific genes influence the quantitative levels of circulating metabolites and thereby impact physiological function.
Systemic Health and Disease Risk
Section titled “Systemic Health and Disease Risk”Genetic factors contribute significantly to the susceptibility and progression of various systemic health conditions, particularly cardiovascular diseases and metabolic disorders. Genetic associations have been identified for subclinical atherosclerosis in major arterial territories[19]indicating a genetic predisposition to this common precursor of heart disease. Furthermore, favorable alterations in plasma lipid profiles, such as those conferred by null mutations inAPOC3, are linked to apparent cardioprotection and a reduced risk of coronary heart disease.[14]Multiple genetic loci are known to influence lipid concentrations, collectively impacting the overall risk of coronary artery disease.[2]
Beyond direct disease mechanisms, genetic influences extend to various markers of cardiovascular function and physical performance. Genetic variants have been associated with echocardiographic dimensions, brachial artery endothelial function, and treadmill exercise responses[4]reflecting the integral role of genetics in determining cardiac structure, vascular health, and systemic physiological capacity. Disruptions in metabolic homeostasis, such as elevated serum uric acid levels due to variants in the urate transporterSLC2A9, can lead to pathophysiological conditions like gout, demonstrating the systemic and organ-specific consequences of genetic variation on disease development and overall health.[3]
References
Section titled “References”[1] Gieger, C et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, vol. 4, no. 11, 2008, p. e1000282.
[2] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 41, no. 1, 2009, pp. 47-55.
[3] 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.
[4] 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, suppl. 1, 2007, S2.
[5] Yuan, X., et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, vol. 83, no. 5, 2008, pp. 547-554.
[6] Yang, Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet. 8.Suppl 1 (2007): S10.
[7] 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.
[8] Melzer, D, et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet. 4.4 (2008): e1000049.
[9] Pare, G., et al. “Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women.” PLoS Genet, vol. 4, no. 7, 2008, e1000118.
[10] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, suppl. 1, 2007, S10.
[11] Vitart, V et al. “SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.”Nat Genet, vol. 40, no. 4, 2008, pp. 432-6.
[12] McArdle, PF, et al. “Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish.”Arthritis Rheum. 58.9 (2008): 2774-81.
[13] Kooner, JS. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, vol. 40, no. 2, 2008, pp. 149-51.
[14] Pollin, TI et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, no. 5906, 2008, pp. 1492-5.
[15] Burkhardt, R et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, vol. 28, no. 12, 2008, pp. 2071-7.
[16] Kathiresan, S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 40, no. 2, 2008, pp. 161-9.
[17] Doring, A et al. “SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.”Nat Genet, vol. 40, no. 4, 2008, pp. 437-42.
[18] 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. 60-5.
[19] O’Donnell, CJ. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, p. S4.