Cinnamoylglycine
Introduction
Section titled “Introduction”Cinnamoylglycine is a naturally occurring glycine conjugate, a compound formed when cinnamic acid, often derived from dietary sources like cinnamon, is metabolized and joined with the amino acid glycine. This biochemical process typically occurs in the liver as part of the body’s detoxification mechanisms, facilitating the excretion of various organic acids and xenobiotics. As an intermediate metabolite, cinnamoylglycine serves as a measurable indicator of both dietary intake and the efficiency of specific metabolic pathways involved in glycine conjugation.[1]
Biological Basis
Section titled “Biological Basis”The formation of cinnamoylglycine is a key aspect of phase II metabolism, where cinnamic acid undergoes conjugation with glycine. This conjugation renders the compound more water-soluble, aiding in its elimination from the body. The levels of cinnamoylglycine in bodily fluids, such as serum, reflect the activity of enzymes responsible for this conjugation pathway, as well as the availability of its precursors. The field of metabolomics, which involves the comprehensive measurement of endogenous metabolites, helps to provide a functional readout of the physiological state and can identify genetic variants that influence the homeostasis of such compounds.[1]
Clinical Relevance
Section titled “Clinical Relevance”Variations in cinnamoylglycine levels can be influenced by genetic factors, dietary habits, and the presence of certain diseases. Genome-wide association studies (GWAS) aim to identify genetic polymorphisms associated with changes in metabolite profiles, including cinnamoylglycine concentrations in human serum.[1]By linking specific genetic variants to these biochemical measurements, researchers can gain insights into underlying disease-causing mechanisms that might not be evident from clinical outcomes alone. Altered levels of cinnamoylglycine could potentially serve as biomarkers for metabolic dysregulation or as indicators of specific dietary exposures and their subsequent processing within the body.
Social Importance
Section titled “Social Importance”Understanding the genetic and environmental factors that contribute to individual variations in cinnamoylglycine levels has broad implications for public health. Such knowledge can contribute to the development of personalized nutrition strategies, more precise diagnostic tools, and targeted therapeutic interventions. By elucidating the metabolic pathways influenced by genetic variants, research into compounds like cinnamoylglycine helps bridge the gap between an individual’s genetic makeup and their observable biochemical phenotype, paving the way for advancements in personalized medicine and disease prevention.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Studies often operate with moderate sample sizes, which can lead to insufficient statistical power to reliably detect genetic associations, especially those with small or modest effect sizes for traits like cinnamoylglycine. This limitation increases the risk of false negative findings, where true genetic influences are inadvertently missed. Conversely, the vast number of statistical tests performed in genome-wide association studies (GWAS) heightens the probability of identifying false positive associations, necessitating rigorous statistical correction and independent validation.[2]
Many GWAS rely on genotyping arrays that cover only a subset of all known single nucleotide polymorphisms (SNPs), potentially leading to incomplete genomic coverage and the oversight of important genetic variants or entire genes not present on the array. For instance, non-SNP variants like those inUGT1A1may be missed due to lack of coverage, hindering a comprehensive understanding of a gene’s role. Consequently, the ultimate validation of any genetic association for cinnamoylglycine hinges on successful replication in independent cohorts; without such external validation, reported p-values may represent false positive findings, underscoring the exploratory nature of initial GWAS results.[3]
Generalizability and Phenotype Assessment
Section titled “Generalizability and Phenotype Assessment”The cohorts typically examined in these studies are predominantly composed of individuals of white European descent, often within middle-aged to elderly demographics. This demographic homogeneity restricts the generalizability of findings concerning cinnamoylglycine to younger populations or individuals from other ethnic and racial backgrounds. Without diverse representation, it remains uncertain how identified genetic associations would manifest or apply across different ancestral groups, highlighting a critical gap in understanding the broader applicability of the research.[4]
Limitations also exist in the precise measurement and definition of certain phenotypes. For example, some studies must rely on proxy markers for physiological traits, such as using TSH as an indicator of thyroid function without direct measures of free thyroxine, or cystatin C as a kidney function marker which might also reflect cardiovascular risk. Additionally, the timing of DNA collection, often occurring later in life, can introduce survival bias, as only individuals who lived long enough to participate are included, potentially skewing observed genetic associations for cinnamoylglycine.[4]
Unaccounted Factors and Mechanistic Gaps
Section titled “Unaccounted Factors and Mechanistic Gaps”While studies commonly employ statistical adjustments for known covariates like age, sex, and various health conditions, it remains challenging to account for all potential environmental or gene-environment confounders that could influence cinnamoylglycine levels. Unmeasured or poorly quantified lifestyle factors and complex interactions can obscure or modify genetic effects, contributing to the “missing heritability” phenomenon where identified genetic variants explain only a fraction of the trait’s variation. Moreover, an exclusive focus on multivariable models might inadvertently lead to overlooking important bivariate associations between SNPs and the measured trait.[5]
GWAS primarily identify statistical associations between genetic variants and phenotypes, but they often provide limited direct insight into the underlying biological mechanisms governing a trait like cinnamoylglycine. Simply associating genotypes with clinical outcomes or intermediate phenotypes does not fully elucidate the disease-causing pathways or the functional consequences of specific genetic variants. A fundamental challenge persists in prioritizing significant SNPs for further investigation and translating statistical associations into a comprehensive understanding of biological function and disease etiology.[2]
Variants
Section titled “Variants”CPS1(Carbamoyl Phosphate Synthetase 1) is a crucial enzyme in the urea cycle, primarily active in the mitochondria of liver and intestinal cells. Its fundamental role is to convert ammonia into carbamoyl phosphate, initiating the detoxification pathway for excess nitrogen generated from protein metabolism.[6] Variants like rs1047891 in CPS1can influence the efficiency of this essential cycle, potentially affecting ammonia levels and the body’s overall nitrogen balance. Disruptions in nitrogen metabolism can have widespread effects, impacting how the body handles various compounds, including those involved in detoxification pathways such as cinnamoylglycine. Cinnamoylglycine, a glycine conjugate, reflects dietary intake of cinnamates or microbial activity, and its excretion is often linked to pathways of xenobiotic metabolism and amino acid conjugation.
TBX10 (T-box transcription factor 10) belongs to a gene family vital for orchestrating embryonic development, particularly in the formation of diverse tissues and organs. Transcription factors like TBX10 are fundamental regulators of gene expression, controlling the production of proteins essential for cellular function and differentiation by binding to specific DNA sequences. [6] While a direct connection between TBX10and cinnamoylglycine metabolism is not immediately apparent, its involvement in extensive regulatory networks suggests that variants such asrs1531514 could indirectly affect broader metabolic pathways, cellular stress responses, or the integrity of organ systems responsible for processing and excreting metabolites. Such genetic variations contribute to the intricate interplay of factors that shape an individual’s unique metabolic profile and susceptibility to various conditions.
The SLC44A5 - ACADM genomic region, which includes variants like rs749583309 , encompasses genes with distinct yet metabolically significant functions. SLC44A5 (Solute Carrier Family 44 Member 5) encodes a protein involved in choline transport, a nutrient critical for maintaining cell membrane integrity, synthesizing neurotransmitters, and regulating lipid metabolism. Adjacent to this, ACADM (Acyl-CoA Dehydrogenase, Medium Chain) is a pivotal enzyme in the mitochondrial beta-oxidation pathway, responsible for breaking down medium-chain fatty acids to generate energy. [6] Genetic variations within or near ACADMcan impair the efficiency of fatty acid oxidation, potentially leading to metabolic disorders like Medium-chain Acyl-CoA Dehydrogenase Deficiency, which impacts energy production and can result in metabolic crises. Given that cinnamoylglycine is a metabolite often linked to detoxification and energy metabolism, dysfunctions in fatty acid oxidation could indirectly influence its production or excretion, indicating broader metabolic stresses or altered availability of substrates for conjugation pathways.
AFF3 (AF4/FMR2 Family Member 3) functions as a transcriptional coactivator, playing a role in chromatin remodeling and gene regulation, with implications for developmental processes and immune system function. Variants such as rs148422820 in AFF3 may alter its regulatory activity, potentially affecting the expression of numerous downstream genes. [6]This gene has been associated with autoimmune diseases, underscoring its importance in maintaining immune system balance. Although not directly involved in the synthesis or breakdown of cinnamoylglycine, alterations in a broad transcriptional regulator likeAFF3could influence systemic inflammation, nutrient sensing, or detoxification capacities. These factors, in turn, might indirectly modulate the metabolic environment in which cinnamoylglycine is produced and processed, highlighting the complex genetic contributions to individual metabolic responses.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs1047891 | CPS1 | platelet count erythrocyte volume homocysteine measurement chronic kidney disease, serum creatinine amount circulating fibrinogen levels |
| rs1531514 | TBX10 | cinnamoylglycine measurement |
| rs749583309 | SLC44A5 - ACADM | cinnamoylglycine measurement |
| rs148422820 | AFF3 | cinnamoylglycine measurement |
Causes
Section titled “Causes”Genetic Determinants of Metabolite Profiles
Section titled “Genetic Determinants of Metabolite Profiles”The concentration of cinnamoylglycine in human serum is understood to be influenced by genetic determinants, which are identified through genome-wide association (GWA) studies. These studies systematically screen the human genome to find genetic variants that significantly alter the homeostasis of various metabolites, including cinnamoylglycine.[1] By identifying these “genetically determined metabotypes,” researchers gain insights into the specific pathways and biological processes that are under genetic control, thereby contributing to a functional understanding of complex diseases. The overall goal is to link specific genetic polymorphisms to their effects on biochemical measurements, providing a detailed view of how inherited factors contribute to an individual’s metabolic profile.
Interplay of Genes and Environment
Section titled “Interplay of Genes and Environment”Beyond direct genetic effects, the regulation of cinnamoylglycine levels also involves intricate gene-environment interactions. Metabolomics research, particularly when integrated with genome-wide association studies, is pivotal for investigating how genetic predispositions interact with various environmental factors to shape an individual’s metabolic state.[1]This approach allows for a more comprehensive understanding of how external influences, such as diet or lifestyle, might modulate the expression or activity of genes involved in cinnamoylglycine metabolism. Such interactions are crucial for elucidating the complex etiology of common diseases, where both inherited factors and environmental triggers play significant roles in determining an individual’s biochemical phenotype.
Biological Background
Section titled “Biological Background”Molecular Mechanisms of Metabolite Transport and Metabolism
Section titled “Molecular Mechanisms of Metabolite Transport and Metabolism”Metabolites represent the functional readout of the physiological state of the human body, with their concentrations in body fluids like serum providing crucial insights into underlying biological processes. [1] The maintenance of metabolite homeostasis involves intricate molecular and cellular pathways, including specific transporter proteins that facilitate their movement across cell membranes. For instance, the SLC2A9 gene, also known as GLUT9, encodes a facilitative glucose transporter family member that plays a crucial role in regulating serum urate concentrations and its excretion.[7]Another key transporter, the renal urate anion exchanger encoded bySLC22A12, also contributes significantly to controlling blood urate levels.[8]
Beyond transport, metabolic processes involve a network of enzymes that catalyze the synthesis, breakdown, and modification of various biomolecules. For example, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is central to the mevalonate pathway, a critical route for cholesterol synthesis. [9] Similarly, enzymes like lecithin:cholesterol acyltransferase (LCAT) are essential for lipid metabolism, and deficiencies can lead to specific syndromes. [6] The proper functioning of these enzymes and transporters is fundamental to cellular health and the overall metabolic balance within an organism.
Genetic Regulation of Metabolic Phenotypes
Section titled “Genetic Regulation of Metabolic Phenotypes”Genetic mechanisms exert significant control over the levels of circulating metabolites, with genome-wide association studies (GWAS) identifying numerous genetic variants that associate with quantitative traits such as metabolite concentrations. [1] These genetic polymorphisms can influence gene functions, including the expression patterns of genes encoding enzymes and transporters, or even impact regulatory elements that control their activity. For instance, variations in SLC2A9have been shown to influence uric acid concentrations, sometimes with pronounced sex-specific effects.[10]
Regulatory networks often involve complex interactions, where genetic variants can affect key biomolecules like transcription factors or lead to changes in mRNA processing, such as alternative splicing. Common single nucleotide polymorphisms (SNPs) inHMGCR, for example, are associated with low-density lipoprotein cholesterol (LDL-C) levels and can affect the alternative splicing of exon 13, thereby influencing the production of the enzyme.[9] Other genes, like MLXIPL, have been identified through genome-wide scans as influencing plasma triglyceride levels, highlighting the broad genetic architecture underlying metabolite homeostasis.[11]
Tissue-Specific Roles and Systemic Homeostasis
Section titled “Tissue-Specific Roles and Systemic Homeostasis”The regulation of metabolite levels involves intricate tissue interactions and organ-specific effects, which collectively contribute to systemic homeostasis. For example, the kidneys play a critical role in maintaining uric acid balance through processes of reabsorption and excretion, influenced by transporters likeSLC2A9 and SLC22A12. [7] The liver is another vital organ for metabolism, being the primary site for cholesterol synthesis regulated by enzymes such as HMGCR, and for the processing of various lipids and other metabolites. [9]
The coordinated function of these organs ensures that metabolite concentrations in the blood and other body fluids remain within a healthy range. Disruptions in this delicate balance, whether due to genetic predispositions or environmental factors, can have widespread systemic consequences, impacting various physiological systems. Understanding these tissue-specific contributions and their integration is essential for comprehending the overall regulation of metabolite profiles in the human body.
Pathophysiological Consequences of Dysregulated Metabolism
Section titled “Pathophysiological Consequences of Dysregulated Metabolism”Dysregulation of molecular and cellular pathways involved in metabolite metabolism and transport can lead to significant pathophysiological processes and contribute to various diseases. For example, elevated serum uric acid levels, often influenced by genetic variants in transporters likeSLC2A9, are a primary cause of gout.[7]Similarly, abnormal concentrations of lipids, such as high LDL-C or triglycerides, are well-established risk factors for coronary artery disease and other cardiovascular conditions.[6]
Metabolomics provides a functional readout that can identify intermediate phenotypes more directly related to disease etiology, offering insights into underlying molecular disease-causing mechanisms.[1] Disruptions in homeostatic mechanisms, such as those governing lipid metabolism or the processing of fatty acids, can manifest as conditions like medium-chain acyl-CoA dehydrogenase deficiency, highlighting the critical link between precise metabolic control and health. [1]The study of genetic variants associated with these metabolic disruptions offers a pathway to understanding disease risk and progression.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Metabolic Interplay and Regulation
Section titled “Metabolic Interplay and Regulation”Cinnamoylglycine is an endogenous metabolite whose concentrations in human serum are subject to genetic influence.[1] The comprehensive measurement of such metabolites, a field known as metabolomics, provides a functional readout of the physiological state, revealing how genetic variants impact the homeostasis of key organic compounds like lipids, carbohydrates, and amino acids. [1] This includes the direct involvement in metabolite conversion modification, which can be influenced by metabolic regulation such as flux control within biosynthesis and catabolism pathways. [1] The genetic architecture of these metabolites, including those involved in fatty acid metabolism like the _FADS1_ _FADS2_ gene cluster, underscores the intricate regulatory landscape governing metabolic flux and biosynthesis pathways. [1]
Genetic Modulation of Metabolite Homeostasis
Section titled “Genetic Modulation of Metabolite Homeostasis”Genetic variants play a significant role in modulating the levels of metabolites, including cinnamoylglycine, by affecting the underlying biochemical pathways.[1] Genome-wide association studies (GWAS) identify polymorphisms that influence the homeostasis of various metabolites, providing insights into the specific genes involved in their synthesis, breakdown, or transport. [1] For instance, genetic variations in genes such as _HMGCR_, known to affect alternative splicing and thus protein function related to lipid metabolism, illustrate how gene regulation directly impacts metabolite profiles.[9] Similarly, variants within the _SLC2A9_ (_GLUT9_) gene are associated with serum uric acid levels, demonstrating genetic control over metabolite transport and concentration.[8]
Network Interactions in Physiological Function
Section titled “Network Interactions in Physiological Function”The physiological impact of metabolites like cinnamoylglycine extends beyond individual reactions, integrating into a complex human metabolic network characterized by extensive pathway crosstalk and hierarchical regulation.[1] Genetic variants that alter metabolite homeostasis offer a detailed view into these network interactions, revealing how changes in one metabolic pathway can propagate and affect others. [1] This systems-level integration approach, combining genotyping with metabolotyping, allows for a more comprehensive understanding of the functional consequences of genetic variations and their emergent properties within the broader biological system. [1]Such an integrated view is crucial for dissecting the intricate interplay between genes, environment, and metabolism, particularly in the context of complex disease etiology.[1]
Dysregulation in Complex Disease Pathogenesis
Section titled “Dysregulation in Complex Disease Pathogenesis”Dysregulation of metabolic pathways, often influenced by genetic predispositions, is a key mechanism in the pathogenesis of various complex diseases. [1]Altered levels of metabolites, including those associated with cinnamoylglycine, can serve as intermediate phenotypes that are more directly related to disease etiology than clinical outcomes alone.[1]For example, genetic loci influencing lipid concentrations are strongly linked to the risk of coronary artery disease and polygenic dyslipidemia, highlighting how perturbations in metabolic pathways contribute to disease.[6]Similarly, variants affecting triglyceride levels or serum uric acid (e.g., in genes like_SLC2A9_) are implicated in conditions such as type 2 diabetes and gout, respectively, providing potential therapeutic targets for intervention.[12]
Clinical Relevance
Section titled “Clinical Relevance”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] Benjamin, Emelia J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. 74.
[3] Yang, Qiong, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, 2007, p. 72.
[4] Hwang, Shih-Jen, et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. 53. PubMed, PMID: 17903292.
[5] Melzer, David, et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genetics, vol. 4, no. 5, 2008, e1000072.
[6] 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.
[7] 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. 432–437.
[8] 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.
[9] 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. 11, 2008, pp. 2078–2084.
[10] Doring, A., et al. “SLC2A9 Influences Uric Acid Concentrations with Pronounced Sex-Specific Effects.”Nat Genet, vol. 40, no. 4, 2008, pp. 430–431.
[11] Kooner, J. S., et al. “Genome-Wide Scan Identifies Variation in MLXIPL Associated with Plasma Triglycerides.” Nat Genet, vol. 40, no. 2, 2008, pp. 149–151.
[12] 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. PubMed, PMID: 17463246.