Amino Acid

Amino acids are fundamental organic compounds that serve as the building blocks of proteins, playing crucial roles in virtually all biological processes within the human body. Beyond their structural functions, they are involved in neurotransmitter synthesis, hormone production, energy metabolism, and immune function. The precise regulation of amino acid levels is vital for maintaining cellular homeostasis and overall physiological health.

Biological Basis

The body obtains amino acids through dietary intake and endogenous synthesis. Essential amino acids cannot be synthesized by the body and must be acquired through diet, while non-essential amino acids can be produced internally. The levels of amino acids in the blood and other bodily fluids are influenced by a complex interplay of genetic and environmental factors. Research indicates that common genetic variations can significantly impact biochemical parameters, including amino acid levels, that are routinely measured in clinical settings.^[1]For instance, studies have shown that genetic loci are associated with levels of non-essential amino acids, suggesting a stronger influence of inherited factors on these molecules. Conversely, clinical factors such as diet and lifestyle tend to explain a greater proportion of the variation in essential amino acid levels, reflecting their primary dietary origin.^[2]This distinction highlights the balance between inherited (endogenous) and dietary (environmental) contributions to an individual’s amino acid profile.^[2]

Clinical Relevance

Measuring amino acid levels in biological samples, such as plasma, is a valuable diagnostic and monitoring tool in medicine. Aberrant amino acid concentrations can be indicative of various metabolic disorders, nutritional deficiencies, liver or kidney disease, and even certain cancers. For example, elevated levels of specific amino acids can signal inborn errors of metabolism in newborns, allowing for early intervention. Monitoring amino acid profiles can also be crucial in managing patients with chronic diseases or those undergoing specialized nutritional therapies. The identification of genetic loci associated with amino acid levels further opens avenues for understanding disease susceptibility and progression at a molecular level.^[2]

The ability to accurately measure amino acid levels holds significant social importance, contributing to personalized medicine and public health initiatives. Understanding an individual’s unique amino acid profile, influenced by both genetics and lifestyle, can lead to tailored dietary recommendations and more precise disease prevention strategies. Early detection of metabolic imbalances through amino acid screening can prevent severe health complications, particularly in pediatric populations. Furthermore, insights gained from large-scale studies linking genetic variations to amino acid levels can inform the development of novel therapeutic targets and biomarkers for a wide range of conditions, ultimately improving health outcomes and quality of life for many individuals.

Limitations

Understanding the genetic architecture underlying amino acid levels is crucial, yet several limitations inherent in current research methodologies and study designs warrant careful consideration when interpreting findings. These limitations span statistical power, population generalizability, and the complex interplay of genetic and environmental factors.

Study Design and Statistical Robustness

Many genetic association studies, including those on amino acid levels, are often limited by sample sizes that may not be sufficiently large to detect genetic variants with small effect sizes, which are characteristic of complex traits. While meta-analyses combine data from multiple cohorts to increase power, the overall sample sizes for some specific amino acid traits or in particular sub-analyses can still be modest, potentially leading to an underestimation of the full genetic landscape.^[3] Furthermore, findings from initial discovery analyses may be subject to the “winner’s curse,” where effect sizes for significant variants are overestimated, leading to overly optimistic P-values and challenges in replication.^[4] Rigorous quality control measures, including correction for genomic inflation factors and careful SNP exclusion criteria, are essential to minimize spurious associations arising from systematic differences or genotyping inaccuracies, but these processes themselves involve trade-offs and are not infallible.^[5]

Population Diversity and Phenotype Assessment

A significant limitation in the generalizability of genetic findings for amino acid levels stems from the predominant focus on populations of European ancestry in many large-scale genetic studies. This imbalance means that findings may not be directly transferable to or fully representative of individuals from other ancestral backgrounds, leading to health disparities and incomplete understanding of trait etiology across diverse populations.^[6] Moreover, even when multi-ancestry analyses are performed, non-European cohorts often have smaller sample sizes, which can necessitate less stringent quality control filters or limit the power to detect associations unique to those groups.^[6]Beyond population considerations, the precise of amino acid levels can vary across studies, with differences in assay methodologies, sample collection protocols, or the biological matrix analyzed (e.g., plasma versus other tissue levels), potentially introducing heterogeneity and complicating the robust meta-analysis of results.^[7]

Environmental and Genetic Complexity

Amino acid levels are highly influenced by a myriad of non-genetic factors, including dietary intake, nutritional status, lifestyle choices, and underlying health conditions, which can confound or modify genetic associations. The intricate interplay between genetic predispositions and environmental exposures (gene-environment interactions) is often not fully captured or adequately modeled in current study designs, leading to an incomplete picture of the factors driving individual variation in amino acid profiles. Despite the identification of specific genetic variants, these typically explain only a small fraction of the total heritable variation in amino acid levels, a phenomenon known as “missing heritability”.^[7] This suggests that a substantial proportion of the genetic influence remains unexplained, possibly due to the contributions of rare variants, complex epistatic interactions, or epigenetic mechanisms that are not routinely assessed in standard genome-wide association studies.

Variants

The genetic landscape influencing amino acid levels involves a diverse set of genes and their variants, impacting metabolic pathways from branched-chain amino acid breakdown to urea cycle function. ThePPM1K-DT locus, encompassing variants such as rs10018448 , rs1440581 , and rs7678928 , is linked to the PPM1K gene, which encodes a protein phosphatase critical for the catabolism of branched-chain amino acids (BCAAs). PPM1Khelps regulate the activity of the branched-chain α-keto acid dehydrogenase complex, a key enzyme in breaking down leucine, isoleucine, and valine.^[8] Variations in this region can therefore alter the efficiency of BCAA metabolism, potentially affecting their plasma concentrations, which are recognized indicators of metabolic health. Similarly, variants rs2238732 and rs5747934 within the PRODHgene are relevant to amino acid profiles, asPRODH encodes proline dehydrogenase, an enzyme vital for the breakdown of proline. This process contributes to cellular energy and redox balance, and genetic variations can impact proline levels and related metabolic pathways points through the human blood plasma proteome.

The CPS1 gene, with its associated variant rs715 , plays a central role in the urea cycle by encoding carbamoyl phosphate synthetase 1. This mitochondrial enzyme catalyzes the initial step of ammonia detoxification, converting ammonia and bicarbonate into carbamoyl phosphate.^[8] Genetic variations in CPS1can affect the efficiency of this critical cycle, leading to altered levels of ammonia and intermediates like arginine and ornithine, thereby impacting overall amino acid homeostasis. Additionally, theCPS1 - RPS27P10 intergenic region, including variants rs12613336 , rs4673546 , and rs10172053 , may collectively influence CPS1 gene expression or function. The ASPG gene, with variant rs1744297 , and the ASPG - MIR203A locus, containing rs61997624 , are involved in asparagine metabolism.ASPGencodes asparaginase, an enzyme that converts asparagine into aspartate and ammonia, thus regulating asparagine availability for protein synthesis and other metabolic processes.^[3] The rs1260326 variant in the GCKRgene is associated with the glucokinase regulatory protein, which modulates the activity of glucokinase, a key enzyme in glucose metabolism within the liver and pancreas. This regulatory role extends to broad energy metabolism, indirectly influencing amino acid catabolism and synthesis through interconnected pathways like glycolysis.^[8] Consequently, variations in GCKRcan impact plasma levels of glucose, lipids, and amino acids. TheKIF26A-DT locus, represented by rs12587001 , is a divergent transcript of a kinesin family member. While kinesins are known for their roles in intracellular transport, such pseudogenes can influence the expression of protein-coding genes or perform independent regulatory functions, potentially affecting cellular processes that indirectly modulate nutrient metabolism. Lastly, the CLEC18C gene, with variant rs370014171 , belongs to the C-type lectin domain family, which are proteins typically involved in immune responses and cell recognition points through the human blood plasma proteome. Although a direct role in amino acid metabolism is not immediately clear, immune and inflammatory pathways can profoundly alter metabolic states and nutrient utilization, suggesting an indirect influence on amino acid profiles.

Key Variants

RS ID	Gene	Related Traits
rs10018448 rs1440581 rs7678928	PPM1K-DT	alpha-hydroxyisovalerate isoleucine leucine amino acid valine
rs1744297	ASPG	amino acid strand of hair color asparagine X-23739
rs61997624	ASPG - MIR203A	amino acid
rs12613336 rs4673546	CPS1 - RPS27P10	amino acid glomerular filtration rate
rs715	CPS1	circulating fibrinogen levels plasma betaine eosinophil percentage of leukocytes platelet crit macular telangiectasia type 2
rs12587001	KIF26A-DT	amino acid asparagine
rs2238732 rs5747934	PRODH	amino acid proline amount valine body height saturated fatty acids to total fatty acids percentage
rs370014171	CLEC18C	leucine pyruvate amino acid valine glutamine
rs10172053	CPS1 - RPS27P10	creatine amount glycine amino acid glomerular filtration rate
rs1260326	GCKR	urate total blood protein serum albumin amount coronary artery calcification lipid

Defining Amino Acid Profiling and Approaches

Amino acid profiling refers to the systematic and identification of amino acids and related metabolites within biological samples, providing a comprehensive view of an individual’s metabolome.^[2]This approach extends beyond basic amino acids to include amino acid derivatives, urea cycle intermediates, nucleotides, and other positively charged polar metabolites.^[2] Operationally, such measurements often involve collecting blood samples after an overnight fast, followed by immediate centrifugation and storage at −80°C until the assay is performed.^[2] A typical might utilize a small plasma volume, such as 10 µL, for the profiling of these specific metabolite groups.^[2] This precise methodology ensures standardization and minimizes variability in metabolite concentrations, which is crucial for robust scientific and clinical interpretation.

Classification and Clinical Significance of Amino Acids

Amino acids are broadly classified into essential and non-essential categories, a distinction with significant implications for understanding metabolic health and disease.^[2]Essential amino acids are those that cannot be synthesized by the body and must be obtained through diet, while non-essential amino acids can be synthesized endogenously. Studies indicate that clinical factors tend to explain a greater proportion of variation in essential amino acid levels compared to non-essential amino acids, suggesting stronger environmental and dietary influences on the former.^[2] Conversely, non-essential amino acids often show a higher genetic contribution to their variability, reflecting the interplay of inherited and environmental factors on these small molecules.^[2]This classification is vital for interpreting metabolite profiling results, as abnormal levels of specific amino acid types can indicate dietary deficiencies, metabolic disorders, or genetic predispositions.

Key Terminology and Criteria

Key terminology in amino acid analysis includes “metabolite profiling,” which encompasses the broader study of small molecules in biological systems, and specific terms like “amino acid derivatives” and “urea cycle intermediates” that denote related compounds often measured alongside amino acids.^[2] The “metabolome” refers to the complete set of small-molecule chemicals found within a biological sample. criteria are critical for ensuring data quality and comparability across studies; for instance, collecting blood samples after an overnight fast is a common standard to minimize dietary influence on metabolite levels.^[2]The volume of plasma used, such as 10 µL for positively charged metabolites, also constitutes a critical part of the operational definition for precise and reproducible amino acid.^[2]

Amino Acid Metabolism and Homeostasis

Amino acids are fundamental organic molecules that serve as the building blocks for proteins, crucial for virtually all cellular functions and structural components within the human body. Beyond their role in protein synthesis, amino acids participate in a myriad of metabolic processes, acting as precursors for neurotransmitters, hormones, and other critical biomolecules. The body meticulously regulates the circulating levels of these molecules to maintain a state of homeostasis, a dynamic equilibrium essential for physiological health.^[8] This complex regulation involves a network of enzymes, transporters, and signaling pathways that govern their synthesis, degradation, and utilization across various tissues.

A key distinction in amino acid biology is between essential and non-essential amino acids. Essential amino acids cannot be synthesized endogenously and must be acquired through dietary intake, whereas non-essential amino acids can be manufactured by the body from other metabolic intermediates.^[2]This difference significantly impacts their regulation; clinical factors, such as diet and environmental influences, explain a greater proportion of the variation in essential amino acid levels compared to non-essential amino acids, which show a stronger inherited component.^[2]Consequently, monitoring amino acid profiles provides a functional readout of an individual’s nutritional status and overall metabolic state.^[8]

Genetic Regulation of Amino Acid Levels

The levels of amino acids in the body are significantly influenced by an individual’s genetic makeup, with specific genetic variants contributing to their observed concentrations. Genome-wide association studies (GWAS) have successfully identified numerous genetic loci linked to the plasma levels of various metabolites, including amino acids.^[2] These studies have shown that genetic variants can associate with changes in the homeostatic balance of amino acids, providing insights into the inherited components governing their metabolism.^[8] Research has uncovered genome-wide significant findings for several non-essential amino acids, highlighting the substantial endogenous, or inherited, contribution to their variability.^[2]These genetic associations implicate variations in genes that encode critical enzymes involved in amino acid synthesis or breakdown, or transporters responsible for their cellular uptake and efflux. The identification of 31 discrete genetic loci, some of which are associated with multiple metabolite traits, underscores the complex genetic architecture underlying amino acid regulation and their interconnectedness within metabolic networks.^[2]

Systemic Influence and Physiological Readout

The concentrations of amino acids in systemic circulation, such as in blood serum or plasma, serve as a comprehensive functional readout of the physiological state of the entire human body.^[8]This reflects the integrated activity of various tissues and organs, each contributing uniquely to the overall amino acid pool. For instance, the liver is a central hub for amino acid metabolism, performing deamination, transamination, and synthesis, while muscles are primary sites for branched-chain amino acid metabolism and protein turnover. The kidneys play a vital role in filtering and reabsorbing amino acids, preventing their excessive loss and maintaining plasma concentrations.

Disruptions to the normal functioning of these organs or imbalances in their intricate inter-tissue communication can lead to altered systemic amino acid profiles. Therefore, the comprehensive analysis of these endogenous metabolites offers a powerful means to assess metabolic health, identify organ-specific effects, and understand the systemic consequences of various biological processes, ranging from nutrient assimilation to disease progression.^[8]

Clinical Relevance and Homeostatic Disruptions

Variations in amino acid levels are not merely markers of metabolic activity but can also indicate homeostatic disruptions and are relevant to various pathophysiological processes. The interplay between genetic predispositions and environmental factors, such as diet and lifestyle, significantly shapes an individual’s amino acid profile. While genetic factors often explain a notable portion of the variation, particularly for non-essential amino acids, clinical factors contribute more significantly to the variability of essential amino acids.^[2] This differential contribution emphasizes the combined impact of inherited traits and external influences on metabolic health.

Understanding the factors that modulate amino acid levels, including specific genetic variants and broader clinical variables, is crucial for unraveling the mechanisms underlying disease development and progression. The ability of metabolomics to provide a detailed functional readout of the body’s physiological state makes the comprehensive assessment of amino acids an invaluable tool for early detection, diagnosis, and monitoring of metabolic disorders, developmental anomalies, and other conditions characterized by altered amino acid homeostasis.^[8]

Metabolic Pathways and Homeostasis

Amino acid levels are dynamically regulated within the body through a series of interconnected metabolic pathways encompassing biosynthesis, catabolism, and interconversion. These pathways are essential for maintaining amino acid homeostasis, ensuring a steady supply for critical biological processes such as protein synthesis, neurotransmitter production, and as substrates for energy metabolism.^[8] The precise control of metabolic flux through these pathways is paramount, preventing both deficiencies and toxic accumulations that could disrupt cellular function. This intricate balance is a fundamental aspect of an organism’s physiological state.

Genetic and Post-Translational Regulation

The regulation of amino acid metabolism is profoundly influenced by both genetic factors and rapid post-translational mechanisms. Genetic variants can affect the expression levels or catalytic efficiency of enzymes and transporters crucial for amino acid processing, thereby altering their steady-state concentrations.^[8]Beyond gene regulation, cellular control also involves post-translational modifications of metabolic enzymes and allosteric control, where binding of metabolites at sites distinct from the active site can rapidly modulate enzyme activity. These regulatory mechanisms collectively ensure that amino acid availability is finely tuned to meet immediate cellular demands and respond to environmental changes.

Systems-Level Metabolic Networks

Amino acid metabolism operates not in isolation but as an integral part of broader, interconnected metabolic networks across cells and tissues.^[9] A systems-level approach, incorporating comprehensive metabolic network reconstructions and tools like KEGG (Kyoto Encyclopedia of Genes and Genomes) and Gene Ontology, is vital for deciphering the complex pathway crosstalk and network interactions that define cellular metabolism.^[10]This holistic perspective allows for the identification of hierarchical regulation and emergent properties, where the behavior of the entire metabolic system differs from the sum of its individual components. Understanding these systemic interactions is crucial for a complete picture of amino acid dynamics.

Physiological Significance and Disease Mechanisms

Alterations in amino acid profiles, often influenced by genetic predispositions, serve as a critical functional readout of an individual’s physiological state.^[8]Dysregulation within amino acid pathways can manifest as metabolic imbalances, which are frequently associated with various disease-relevant mechanisms. The comprehensive analysis of amino acids through metabolomics can reveal pathway dysregulation, uncover compensatory mechanisms that the body employs to mitigate stress, and identify potential therapeutic targets for intervention.^[8]Thus, understanding the pathways and mechanisms governing amino acid levels is pivotal for diagnostics and the development of personalized medical strategies.

Amino Acid Profiling in Risk Assessment and Diagnosis

Amino acid profiling, which includes the comprehensive of amino acids and their derivatives, serves as a functional readout of an individual’s physiological state, offering critical insights for disease risk assessment and diagnosis.^[8]For instance, metabolomic profiling has identified specific metabolite clusters, such as short-chain dicarboxylacylcarnitines (SCDA), long-chain dicarboxylacylcarnitines (LCDA), and medium-chain acylcarnitines (MCA), as novel biomarkers for cardiovascular disease (CVD) risk.^[11] These measurements can therefore contribute significantly to early risk assessment, facilitating the identification of high-risk individuals who may benefit from targeted prevention strategies or early diagnostic interventions.

The ability to measure amino acids and other polar analytes in plasma, typically collected after an overnight fast, provides a detailed snapshot of various metabolic pathways.^[2] Perturbations in these profiles can indicate underlying metabolic dysregulation or increased susceptibility to specific diseases. Integrating these metabolomic insights with established clinical factors enhances diagnostic precision and refines risk stratification models, paving the way for more personalized and proactive approaches in patient care.

Prognostic Indicators and Therapeutic Guidance

Amino acid profiles possess substantial prognostic value, aiding in the prediction of disease outcomes, progression, and even long-term implications. Research has shown that specific metabolite factors, including acylcarnitines, can be associated with time-to-death, as demonstrated through Cox-proportional hazards modeling in large cohorts.^[11] Such prognostic indicators are invaluable for clinicians, providing foresight into the likely trajectory of a patient’s condition and enabling the implementation of more proactive and tailored management plans.

Furthermore, amino acid measurements are instrumental for monitoring disease progression and evaluating the effectiveness of therapeutic interventions. By tracking changes in particular amino acid levels or their ratios over time, healthcare providers can objectively assess treatment response and adjust therapeutic strategies as necessary. This dynamic monitoring capability supports personalized medicine by allowing for the real-time adaptation of care, which can optimize patient outcomes and potentially mitigate the development of long-term complications.

Genetic and Environmental Influences on Amino Acid Homeostasis

The intricate balance of amino acid levels is shaped by a complex interplay of both genetic and environmental factors, providing crucial avenues for personalized medicine and prevention. Studies indicate that a considerable proportion of the inter-individual variability in amino acid levels is attributable to heritable factors, with non-essential amino acids often exhibiting higher heritability and more identified genome-wide significant genetic loci compared to essential amino acids.^[2] Understanding these inherited predispositions is key to identifying individuals who may be genetically susceptible to specific metabolic imbalances, thus guiding early and targeted prevention strategies.^[8]Conversely, clinical factors such as age, sex, body-mass index, diabetes, smoking status, and prevalent cardiovascular disease account for a greater proportion of the variation observed in essential amino acid levels than in non-essential ones.^[2]This highlights how lifestyle and existing disease states significantly modulate amino acid metabolism. By integrating insights from genetic studies with clinical and environmental data, a more comprehensive risk stratification can be achieved, informing the selection of individualized treatment and prevention approaches, ranging from specific dietary modifications to targeted pharmacological interventions.

Frequently Asked Questions About Amino Acid

These questions address the most important and specific aspects of amino acid based on current genetic research.

1. Does what I eat impact some amino acids more than others?

Yes, absolutely. Your diet has a stronger influence on essential amino acids because your body can’t make them, so you must get them from food. For non-essential amino acids, your body’s own genetic makeup plays a larger role in determining their levels. This highlights the balance between what you eat and your inherited factors.

2. Could my family’s health history affect my amino acid profile?

Yes, your family’s health history can definitely play a role. Common genetic variations passed down in families can significantly impact your amino acid levels. Understanding these inherited factors can help doctors better understand your susceptibility to certain health conditions at a molecular level.

3. Can measuring my amino acids help tailor my diet?

Yes, it can be very helpful! Knowing your unique amino acid profile, which is shaped by both your genetics and lifestyle, allows for more personalized dietary recommendations. This can lead to more precise strategies for disease prevention and optimizing your nutritional intake.

4. If I feel unwell, could it be linked to my amino acids?

Potentially, yes. Unusually high or low levels of certain amino acids can be a sign of various underlying health issues. These can include metabolic disorders, nutritional deficiencies, problems with your liver or kidneys, and even some types of cancer. It’s a valuable clue for doctors.

5. Why do doctors check amino acids in babies?

It’s a critical early screening tool for newborns. Elevated levels of specific amino acids can signal inborn errors of metabolism, which are genetic conditions. Catching these problems early allows doctors to intervene quickly, preventing severe health complications for the baby.

6. Do my daily habits, like exercise, change my amino acid levels?

Yes, your daily habits and lifestyle choices, including exercise, can significantly influence your amino acid levels. Alongside diet and overall health, these non-genetic factors are part of the complex interplay that shapes your unique amino acid profile. It’s not just about your genes!

7. Does my ethnic background influence my amino acid readings?

It can. Many large genetic studies have primarily focused on people of European ancestry, meaning that findings might not fully apply to individuals from other backgrounds. Your genetic ancestry can affect how your body processes and maintains amino acid levels, so interpretations may differ.

8. Is it useful to get my amino acids checked even if I feel fine?

Yes, it can be quite useful for personalized health. Understanding your unique amino acid profile, even without symptoms, can offer insights into your body’s metabolic state. This information can help in developing tailored prevention strategies and optimizing your overall health proactively.

9. Why do genetic tests only explain a little about my amino acids?

That’s a common observation called “missing heritability.” While specific genetic variants are identified, they often only explain a small portion of the total inherited variation in amino acid levels. This suggests that many other factors, like rare genetic variants, complex gene interactions, or epigenetic changes, are also at play.

10. If I have a chronic illness, should I monitor my amino acids?

Yes, monitoring amino acid profiles can be very important if you have a chronic illness. It’s a valuable tool for managing your condition and for guiding specialized nutritional therapies. Keeping an eye on these levels helps doctors ensure your body is functioning as optimally as possible.

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

[1] Wallace, Cathryn, et al. “Genome-Wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia.”American Journal of Human Genetics, vol. 82, no. 1, 2008, pp. 109–119.

[2] Rhee EP, et al. “A genome-wide association study of the human metabolome in a community-based cohort.” Cell Metab, vol. 18, no. 1, 2013, pp. 130-43.

[3] Gialluisi, A., et al. “Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.” Translational Psychiatry, 2019.

[4] Aberg, K. A., et al. “A comprehensive family-based replication study of schizophrenia genes.”JAMA Psychiatry, 2013.

[5] Wellcome Trust Case Control Consortium. “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.” Nature, 2007.

[6] Noordam, R., et al. “Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.” Nature Communications, 2019.

[7] Lemaitre, R. N., et al. “Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.” PLoS Genetics, 2011.

[8] 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, e1000282.

[9] Duarte, N. C., et al. “Global reconstruction of the human metabolic network based on genomic and bibliomic data.” Proc Natl Acad Sci U S A, vol. 104, 2007, pp. 1777–1782.

[10] Krumsiek, J. “Mining the unknown: a systems approach to metabolite identification combining genetic and metabolic information.” PLoS Genet.

[11] Kraus WE, et al. “Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.”PLoS Genet, vol. 10, no. 11, 2014, e1004825.