Ergothioneine
Ergothioneine is a naturally occurring amino acid derivative synthesized by certain bacteria and fungi. Humans obtain this compound primarily through their diet, with mushrooms being a particularly rich source. Its unique chemical structure, featuring a sulfur-containing imidazole ring, distinguishes it as a potent antioxidant.
Biological Basis
Section titled “Biological Basis”Within the body, ergothioneine is actively transported into cells by a specific transporter,SLC22A4, and accumulates in various tissues, including the liver, kidneys, red blood cells, and the lens of the eye. Its primary biological function is to protect cells and their components, such as mitochondrial DNA and proteins, from oxidative damage caused by reactive oxygen species. This cytoprotective role is essential for maintaining cellular health and function, especially in tissues with high metabolic activity or exposure to oxidative stress.
Clinical Relevance
Section titled “Clinical Relevance”Emerging research indicates that ergothioneine may have significant implications for human health, particularly in mitigating chronic diseases associated with oxidative stress and inflammation. Studies are exploring its potential benefits in conditions such as neurodegenerative disorders, cardiovascular diseases, and certain types of cancer. Its ability to combat oxidative damage and support mitochondrial integrity makes it a compound of interest for preventative health strategies and potential therapeutic applications.
Social Importance
Section titled “Social Importance”The recognition of ergothioneine’s health-promoting properties has increased its social importance as a dietary component. As public awareness grows regarding the role of nutrition in health and longevity, foods rich in ergothioneine and ergothioneine supplements are attracting attention. Understanding how genetic variations, such as those in theSLC22A4gene, might influence an individual’s ergothioneine levels or its utilization could lead to personalized dietary recommendations and targeted health interventions aimed at enhancing cellular protection and overall well-being.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Genetic association studies for ergothioneine levels often face limitations related to study design and statistical power. Many investigations rely on moderate sample sizes, which can restrict the ability to detect genetic effects of modest magnitude, potentially leading to false negative findings. This limitation is further compounded by the extensive multiple testing inherent in genome-wide association studies (GWAS), where a conservative alpha level is required, making it challenging to identify variants explaining smaller proportions of phenotypic variation.[1]Furthermore, initial identified associations may exhibit inflated effect sizes, particularly if not rigorously replicated, leading to an overestimation of their true biological impact on ergothioneine levels.[2]
Replication of findings is a fundamental challenge in validating genetic associations with ergothioneine. A significant proportion of initial associations may not replicate in independent cohorts, which can be due to several factors, including false positive results in the discovery phase, differences in cohort characteristics, or inadequate statistical power in replication studies[3]. [4]The use of different marker sets or partial coverage of genetic variation in candidate genes can also hinder replication efforts, potentially missing true associations or causal variants for ergothioneine due to insufficient genomic coverage[1]. [5]
Population Specificity and Phenotype Characterization
Section titled “Population Specificity and Phenotype Characterization”A primary limitation of current research on ergothioneine involves the generalizability of findings, as many studies are predominantly conducted in populations of white European ancestry[3], [6], [7], [8]. [1]Genetic architecture, allele frequencies, and linkage disequilibrium patterns can vary significantly across different ethnic and racial groups, meaning that associations identified in one population may not be directly transferable or have the same effect size in others. This lack of diversity in study cohorts raises concerns about potential population stratification effects and limits the broader applicability of genetic insights into ergothioneine levels across a global population.[8]
Phenotype measurement also presents challenges, particularly when traits like ergothioneine levels are averaged across multiple examinations spanning extended periods. While averaging can aim to reduce regression dilution bias, it may introduce misclassification if different equipment is used or if the underlying assumption that similar genes and environmental factors influence the trait consistently across wide age ranges is not met.[1]Such strategies could inadvertently mask age-dependent genetic effects on ergothioneine, highlighting the need for precise and context-specific phenotypic characterization.
Environmental Influence and Knowledge Gaps
Section titled “Environmental Influence and Knowledge Gaps”The role of environmental factors and their complex interactions with genetic predispositions in determining ergothioneine levels remains largely underexplored. Genetic variants can influence phenotypes in a context-specific manner, with environmental exposures potentially modulating their expression or effect size.[1]Without comprehensive investigations into gene-environment interactions, the full spectrum of factors contributing to the variability of ergothioneine levels remains incomplete, potentially overlooking critical biological pathways and regulatory mechanisms.
Despite advances in identifying genetic loci, a substantial portion of the heritability for complex traits like ergothioneine often remains unexplained, a phenomenon known as “missing heritability”[9]. [1]This indicates that many causal variants, including rare alleles, structural variations, or complex epistatic interactions between genes, have yet to be discovered or fully characterized. Future research needs to employ more comprehensive genomic approaches and functional studies to bridge these knowledge gaps and fully elucidate the intricate genetic architecture underpinning ergothioneine levels.
Variants
Section titled “Variants”Genetic variations play a crucial role in determining individual susceptibility to various health outcomes, including those potentially influenced by the antioxidant ergothioneine. The solute carrier family of genes, particularly members of theSLC22Afamily, are central to the transport of organic cations, a group that includes ergothioneine. For instance, variants inSLC22A4are particularly noteworthy, as this gene encodes OCTN1, a primary transporter responsible for the cellular uptake of ergothioneine.[10]The single nucleotide polymorphism (SNP)rs273913 , associated with SLC22A4 and the long non-coding RNA MIR3936HG, may influence the expression or function of this critical transporter, thereby affecting ergothioneine levels and cellular antioxidant capacity. Similarly,SLC22A5(OCTN2), involved in carnitine transport, andSLC22A16 (OCT6) are other organic cation transporters that, through variants like rs274572 , rs11746555 , rs12210538 , and rs72939920 , could indirectly impact the broader cellular metabolic environment and the availability or utilization of essential compounds, including those that interact with or are protected by ergothioneine.[3] These genetic differences can lead to varying efficiencies in nutrient and metabolite transport, potentially altering cellular resilience against oxidative stress and inflammation.
Other variants impact genes involved in immune response and inflammation, pathways where ergothioneine acts as a protective agent. The long non-coding RNAMIR3936HG, with variant rs273897 , may play a regulatory role, potentially influencing the expression of nearby genes or immune pathways relevant to cellular health. Genes like CARINH (CAR-associated INhibitor of NFKB) and IRF1 (Interferon Regulatory Factor 1), with variants such as rs766751473 and rs6866614 , are critical components of the inflammatory signaling cascade . Variations in these genes can modulate the intensity and duration of inflammatory responses, thereby affecting the cellular demand for antioxidants like ergothioneine. Furthermore, theIFNB1-IFNWP4 region, with variant rs10811465 , is associated with interferon production, a key aspect of antiviral and immunomodulatory responses. [11]Alterations in these pathways could influence the overall cellular environment and the body’s ability to combat stress, highlighting the broader implications for ergothioneine’s cytoprotective functions.
Variants in genes affecting neurological and fundamental cellular functions also carry implications for cellular health and oxidative stress. For instance, RIMS2 (rs10110204 ) is involved in regulating neurotransmitter release, a process highly sensitive to oxidative damage, where ergothioneine’s antioxidant properties are particularly valuable in neuronal protection. Similarly,CACNA1A (rs3764665 ) encodes a subunit of voltage-dependent calcium channels, crucial for neuronal excitability and muscle function; dysregulation of calcium homeostasis is a common feature of cellular stress and neurodegenerative conditions.[12] Genetic variations affecting these channels could influence cellular vulnerability, increasing the protective demand for potent antioxidants. Lastly, OPCML (rs7935421 ), a gene involved in cell adhesion and signal transduction, contributes to cellular integrity and communication, processes that are fundamental to maintaining tissue health and are often compromised under conditions of oxidative stress, underscoring the broad relevance of ergothioneine’s protective role.[13]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs12210538 rs72939920 | SLC22A16 | reticulocyte count blood metabolite level HMBS/PKLR protein level ratio in blood BLVRB/HMBS protein level ratio in blood CA2/HMBS protein level ratio in blood |
| rs274572 rs11746555 | SLC22A5 | ergothioneine measurement |
| rs273913 | SLC22A4, MIR3936HG | serum metabolite level acylcarnitine measurement 3-dehydrocarnitine measurement ergothioneine measurement |
| rs273897 | MIR3936HG | ergothioneine measurement |
| rs766751473 | CARINH | type 1 diabetes mellitus ergothioneine measurement level of dual specificity mitogen-activated protein kinase kinase 6 in blood serum level of cyclin-dependent kinase inhibitor 1 in blood interleukin-5 receptor subunit alpha measurement |
| rs6866614 | IRF1, CARINH | asthma, cardiovascular disease perceived unattractiveness to mosquitos measurement level of bis(5’-adenosyl)-triphosphatase in blood level of Friend leukemia integration 1 transcription factor in blood level of tubulinyl-Tyr carboxypeptidase 1 in blood |
| rs10110204 | RIMS2 | ergothioneine measurement |
| rs3764665 | CACNA1A | ergothioneine measurement |
| rs7935421 | OPCML | ergothioneine measurement |
| rs10811465 | IFNB1 - IFNWP4 | ergothioneine measurement |
References
Section titled “References”[1] 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 Medical Genetics, vol. 8, 2007, p. 56.
[2] Willer, C. J., et al. “Newly Identified Loci That Influence Lipid Concentrations and Risk of Coronary Artery Disease.”Nature Genetics, vol. 40, no. 2, 2008, pp. 161-169.
[3] Benjamin EJ, et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet. 2007.
[4] Sabatti, C., et al. “Genome-Wide Association Analysis of Metabolic Traits in a Birth Cohort From a Founder Population.”Nature Genetics, vol. 41, no. 1, 2009, pp. 35-42.
[5] Yang, Q., 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. 55.
[6] Kathiresan, S., et al. “Common Variants at 30 Loci Contribute to Polygenic Dyslipidemia.” Nature Genetics, vol. 41, no. 1, 2009, pp. 56-65.
[7] Melzer, D., et al. “A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs).” PLoS Genetics, vol. 4, no. 5, 2008, p. e1000072.
[8] 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 Genetics, vol. 4, no. 7, 2008, p. e1000118.
[9] Benyamin, B., et al. “Variants in TF and HFEExplain Approximately 40% of Genetic Variation in Serum-Transferrin Levels.”American Journal of Human Genetics, vol. 84, no. 1, 2009, pp. 60-65.
[10] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.” PLoS Genet. 2008.
[11] Wallace C, et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet. 2008.
[12] Yuan X, et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet. 2008.
[13] Saxena R, et al. “Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.” Science. 2007.