Reduced Glutathione
Background
Section titled “Background”Reduced glutathione (GSH) is a crucial tripeptide composed of the amino acids cysteine, glycine, and glutamate, found in virtually all living cells. It is the active form of glutathione and plays a central role in maintaining cellular health. Often referred to as the “master antioxidant,” GSH is critical for protecting the body against oxidative stress, a process linked to various diseases and aging. Its concentration within cells, particularly in its reduced form, is a key indicator of cellular redox status and overall well-being.[1]
Biological Basis
Section titled “Biological Basis”The primary biological function of reduced glutathione is its role as a major endogenous antioxidant. It directly neutralizes harmful free radicals and reactive oxygen species, preventing damage to cellular components like DNA, proteins, and lipids. Beyond its direct antioxidant action, GSH is a vital cofactor for several detoxification enzymes, including glutathione S-transferases (GST), which facilitate the removal of xenobiotics (foreign compounds) and endogenous toxins from the body. [2]Glutathione is also involved in various other essential cellular processes, including immune function, regulation of gene expression, cell proliferation and apoptosis, protein synthesis, and amino acid transport. The balance between reduced glutathione (GSH) and its oxidized form (GSSG) is maintained by the enzyme glutathione reductase (GSR), ensuring a continuous supply of the active, reduced form. [3] The synthesis of glutathione is primarily regulated by gamma-glutamylcysteine ligase (GCL), the rate-limiting enzyme in the pathway.
Clinical Relevance
Section titled “Clinical Relevance”Imbalances in reduced glutathione levels are associated with a wide range of clinical conditions. Low levels of GSH are frequently observed in diseases characterized by increased oxidative stress and inflammation, such as neurodegenerative disorders (e.g., Parkinson’s disease, Alzheimer’s disease), cardiovascular diseases, chronic inflammatory conditions, liver disease, and certain types of cancer. Research suggests that maintaining optimal GSH levels may offer protective benefits against these conditions and could influence the progression of age-related decline. Consequently, strategies aimed at boosting cellular glutathione, including dietary interventions, supplementation with glutathione precursors like N-acetylcysteine (NAC), or direct glutathione supplementation, are areas of significant therapeutic interest. Genetic variations in genes involved in glutathione synthesis (GCL), metabolism (GSR), and detoxification (GST) can influence an individual’s basal GSH levels and their susceptibility to oxidative stress-related health issues. [3]
Social Importance
Section titled “Social Importance”Reduced glutathione has garnered considerable attention in the health and wellness community due to its perceived role in “detoxification,” anti-aging, and overall vitality. This interest has led to the widespread availability of glutathione supplements in various forms, including oral, liposomal, and intravenous preparations, marketed for their potential to support immune function, enhance energy, and promote healthy aging. There is also a growing public awareness of dietary factors that can influence the body’s natural glutathione production, such as consuming sulfur-rich foods and certain amino acids. The ongoing research into glutathione’s diverse roles in health and disease continues to fuel its social importance as a key molecule for maintaining human well-being and preventing chronic illness.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Studies on complex traits like reduced glutathione are inherently subject to various methodological and statistical challenges. A notable limitation stems from the moderate sample sizes often employed in genome-wide association studies (GWAS), which can result in a lack of power to detect modest genetic associations, thereby increasing the susceptibility to false negative findings.[4] Conversely, the extensive number of statistical tests performed in GWAS carries a significant risk of false positive associations, necessitating stringent significance thresholds and independent replication to validate initial findings. [4] Indeed, meta-analyses suggest that only a minority of reported phenotype-genotype associations are consistently replicated across studies, highlighting the critical need for external validation and the potential for spurious results. [4]
Further complicating the interpretation of results, many protein or metabolite levels, including those related to reduced glutathione, often exhibit non-normal distributions, requiring various statistical transformations to approximate normality for association analyses.[5] While these transformations (e.g., log, Box-Cox, probit) are essential for robust statistical testing, they can influence the interpretation of effect sizes and may obscure nuances in the original data distribution. [5]The use of proxy measures or ratios, such as metabolite concentration ratios to infer enzymatic activity, can reduce variance and increase statistical power, but these indirect measures introduce a layer of abstraction that may not fully capture the direct biological mechanisms influencing reduced glutathione levels.[6]
Generalizability and Phenotypic Nuances
Section titled “Generalizability and Phenotypic Nuances”The generalizability of findings regarding reduced glutathione is often limited by the demographic characteristics of the study populations. Many genomic studies, including those on biomarker traits, have predominantly focused on cohorts composed of individuals of white European ancestry, often of middle-aged to elderly demographic.[5]This lack of ethnic diversity and age representation means that findings may not be directly applicable or transferable to younger populations or individuals of other racial and ethnic backgrounds, leading to an incomplete understanding of genetic influences on reduced glutathione across diverse human populations.[4]
Furthermore, cohort-specific biases, such as survival bias introduced by DNA collection at later examination points in longitudinal studies, can distort observed associations by preferentially including healthier or longer-lived individuals. [4] Differences in assay methodologies and population demographics across various cohorts can also lead to variations in measured trait levels, making direct comparisons and meta-analyses challenging without careful standardization. [7]The metabolic pathways involving reduced glutathione, particularly theGlutathione S-transferase (GST) superfamily genes, are crucial for detoxifying xenobiotics like cigarette smoke, implying that environmental exposures can profoundly modify the phenotype-genotype associations. [8]Therefore, a comprehensive understanding of reduced glutathione requires careful consideration of how genetic predispositions interact with environmental factors.
Causal Inference and Remaining Knowledge Gaps
Section titled “Causal Inference and Remaining Knowledge Gaps”Despite the identification of numerous genetic associations, establishing a causal link between specific genetic variants and reduced glutathione levels remains a significant challenge. Initial associations identified through GWAS require rigorous replication in independent cohorts and, crucially, functional studies to delineate the precise biological mechanisms and confirm causality.[4]Without such functional validation, observed associations, even those with strong statistical support, may merely reflect correlations or linkage disequilibrium with the true causal variant, rather than direct functional effects on reduced glutathione metabolism.
The complexity of reduced glutathione as a biomarker also means that current research may not fully account for all relevant genetic and environmental influences. Important knowledge gaps persist concerning gene-environment interactions, such as the impact of smoking or other xenobiotic exposures onGSTgene activity and subsequent reduced glutathione levels.[8] Future research could benefit from more sophisticated analytical approaches, including stratified analyses and multivariate phenotyping, to uncover these complex interplays. The lack of consistent replication for some findings also highlights underlying complexities, suggesting that other unmeasured genetic, epigenetic, or environmental factors may modify these associations in ways not yet fully understood. [4]
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing various biological processes, including cellular maintenance and antioxidant defense, which are intrinsically linked to levels of reduced glutathione. Pseudogenes, though often considered non-coding and non-functional copies of active genes, can still harbor single nucleotide polymorphisms (SNPs) that may indirectly influence gene expression, RNA stability, or even produce regulatory RNAs, thereby impacting cellular pathways.[5] For instance, variants such as rs4490575 near _ANKRD49P3_, and rs113014964 associated with _PPIAP76_ and _TUBAP10_, could hypothetically modulate the activity of neighboring functional genes or genomic regions. Such modulations might subtly alter cellular responses to stress, which in turn could influence the demand for and regeneration of reduced glutathione, a vital component of the cellular antioxidant system.[9]Maintaining adequate levels of reduced glutathione is essential for detoxifying harmful compounds and mitigating oxidative damage.
The gene _CADM1_ (Cell Adhesion Molecule 1) encodes a protein critical for cell-cell adhesion, signal transduction, and the proper development and function of the nervous system. Variants like rs57734211 within or near _CADM1_ could potentially alter the efficacy of cell adhesion or signaling pathways, influencing cellular integrity and communication. [6]Disruptions in these fundamental cellular processes can lead to increased cellular stress and inflammation, which are known to consume reduced glutathione, thereby affecting the cell’s overall antioxidant capacity and its ability to manage oxidative burden.[9] Changes in _CADM1_ function could, therefore, indirectly impact cellular redox homeostasis.
Another significant gene is _ADARB2_(Adenosine Deaminase RNA Specific B2), which is an RNA editing enzyme responsible for converting adenosine to inosine within double-stranded RNA molecules. This editing process is vital for diversifying gene expression and protein function, particularly within the nervous system.[10] A variant such as rs904963 in _ADARB2_could modify the enzyme’s activity or expression, potentially leading to widespread changes in RNA editing patterns. Such alterations may result in the production of aberrant proteins or affect the regulation of genes involved in metabolic and antioxidant defense pathways. Consequently, an impaired_ADARB2_function could contribute to increased cellular stress and a heightened demand for reduced glutathione, as the body attempts to compensate for compromised cellular resilience.[9]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Signs and Symptoms
Section titled “Signs and Symptoms”Pulmonary Health and Detoxification Capacity
Section titled “Pulmonary Health and Detoxification Capacity”The Glutathione S-Transferase (GST) superfamily genes are critical for the metabolism of xenobiotics, including compounds found in cigarette smoke. [8] Genetic polymorphisms within this family have been linked to significant clinical presentations. For instance, deletions in GSTT1, either alone or in conjunction with GSTM1, have been observed to influence annual changes in lung function measures within population-based cohorts. [8]Furthermore, variations within the human glutathione S-transferase supergene family correlate with an individual’s susceptibility to lung cancer.[9] These findings highlight how genetic predispositions affecting the efficiency of the glutathione system can manifest as compromised detoxification pathways, thereby impacting pulmonary health and increasing the risk for specific diseases.
Hepatic Indicators and Biochemical Assessment
Section titled “Hepatic Indicators and Biochemical Assessment”Gamma-glutamyl transferase (GGT) serves as an objective and measurable biomarker for evaluating aspects related to liver function and, indirectly, the glutathione system. Studies indicate that GGT measurements exhibit good reproducibility, with low intra-assay coefficients of variation. [4] Genetic variants, such as rs4820599 located near the GGT1 gene on chromosome 22q11.23, are strongly associated with plasma GGT levels. [7] However, GGT levels can show considerable inter-individual and inter-population variability, influenced by demographic factors and differences in assay methodologies. [7] Elevated GGT levels are primarily indicative of hepatocyte dysfunction; given the central role of glutathione in hepatic detoxification, alterations in GGT can serve as a diagnostic signal for potential stress on the overall glutathione system. [7]
Causes of Reduced Glutathione
Section titled “Causes of Reduced Glutathione”Genetic Variants Affecting Glutathione Metabolism
Section titled “Genetic Variants Affecting Glutathione Metabolism”Inherited genetic variants play a significant role in an individual’s capacity to maintain optimal glutathione levels. Polymorphisms within the Glutathione S-Transferase (GST) supergene family, including deletions in genes like GSTM1 and GSTT1, are particularly impactful. These enzymes are critical for detoxifying xenobiotics and endogenous harmful compounds through conjugation with glutathione. [9] A complete absence of functional GSTM1 or GSTT1 protein due to these inherited deletions can impair the body’s ability to neutralize toxins, leading to a greater demand for glutathione and potentially resulting in its reduced availability. [8]
Beyond detoxification enzymes, other genes influencing glutathione metabolism also contribute. Genetic variants near the GGT1 gene on chromosome 22q11.23 are strongly associated with plasma gamma-glutamyltransferase (GGT) levels, an enzyme involved in the extracellular breakdown of glutathione. [7] SNPs such as rs4820599 , rs5751901 , and rs6519519 affect GGT activity, and alterations in GGT can influence glutathione turnover and overall systemic concentrations. [7] This highlights a polygenic risk model, where multiple genetic factors can collectively influence the complex trait of glutathione levels, impacting its synthesis, utilization, and degradation pathways. [11]
Environmental Exposures and Gene-Environment Interactions
Section titled “Environmental Exposures and Gene-Environment Interactions”Environmental factors exert substantial influence on glutathione status by increasing its consumption or impairing its synthesis. Exposure to xenobiotics, particularly toxins from sources like cigarette smoke, places a significant burden on the body’s detoxification systems and forces an increase in glutathione utilization. [8]When the rate of glutathione consumption by these environmental stressors surpasses its synthesis capacity, a net reduction in overall glutathione levels occurs. Diet and lifestyle choices, such as inadequate intake of glutathione precursors or excessive toxin exposure, can further exacerbate this imbalance.
The impact of environmental exposures is often amplified by an individual’s genetic makeup, illustrating crucial gene-environment interactions. For instance, individuals carrying deletion polymorphisms in GSTM1 or GSTT1 exhibit a reduced capacity to metabolize and excrete specific environmental toxins. [8] When these genetically predisposed individuals are exposed to xenobiotics like those in cigarette smoke, their impaired detoxification pathways lead to a more significant and rapid depletion of glutathione, consequently increasing oxidative stress and potentially influencing cellular function more severely. [8]
Age-Related Decline and Early Life Influences
Section titled “Age-Related Decline and Early Life Influences”Advancing age is a well-recognized factor contributing to reduced glutathione levels. As individuals age, a natural decline in various physiological functions, including antioxidant defense mechanisms, often occurs.[5]This age-related reduction in glutathione is thought to stem from a combination of decreased synthetic capacity and an increased burden of oxidative stress and chronic inflammation accumulating over a lifetime. Longitudinal studies on aging populations demonstrate the dynamic nature of biomarkers like glutathione throughout the lifespan.[5]
Developmental factors and conditions experienced during early life can also have lasting impacts on an individual’s metabolic and detoxification capacities, thereby influencing glutathione homeostasis later in life. Studies utilizing birth cohorts and focused on specific age groups highlight how early exposures might shape long-term physiological set points.[5]While specific molecular mechanisms like DNA methylation or histone modifications influencing glutathione are not detailed in these studies, the enduring effects of early life environments on complex traits are a recognized phenomenon, suggesting a potential role in establishing baseline glutathione levels.
Biological Background
Section titled “Biological Background”Gamma-Glutamyltransferase and Liver Enzyme Function
Section titled “Gamma-Glutamyltransferase and Liver Enzyme Function”Plasma levels of liver enzymes are important biomarkers reflecting various physiological states and cellular functions. Among these, Gamma-glutamyltransferase (GGT) is a key enzyme that is frequently assessed. While the liver is a primary source, GGT activity detected in the plasma serves as a widely utilized indicator in clinical and research settings. [12] The presence and activity of GGT, alongside other liver enzymes, are integral to metabolic processes and cellular detoxification pathways within the body, providing insights into the overall functioning and health of hepatic cells. These enzymes participate in complex molecular and cellular pathways, contributing to the maintenance of cellular homeostasis.
Genetic Regulation of Liver Enzyme Levels
Section titled “Genetic Regulation of Liver Enzyme Levels”The levels of biochemical liver function tests, including Gamma-glutamyltransferase activity, are significantly influenced by genetic factors. Studies, such as population-based twin studies, have provided evidence for a substantial heritable component contributing to these enzyme levels. [13] Furthermore, genome-wide association studies (GWAS) have successfully identified specific genetic loci that influence the plasma levels of liver enzymes. [7] These findings suggest that variations in gene functions, regulatory elements, or gene expression patterns can dictate an individual’s enzyme activity, forming crucial regulatory networks that govern their physiological concentrations.
Systemic Health Implications and Pathophysiology
Section titled “Systemic Health Implications and Pathophysiology”Elevated plasma levels of liver enzymes, particularly Gamma-glutamyltransferase, are associated with several pathophysiological processes and systemic health issues. Research indicates a link between liver enzymes and an increased risk of developing conditions such as diabetes and cardiovascular disease.[14] Moreover, GGT levels have been identified as a significant factor in long-term survival, suggesting their role extends beyond liver-specific pathology to impact overall health outcomes. [12] The genetic covariation between serum Gamma-glutamyltransferaseactivity and cardiovascular risk factors further highlights its involvement in broader homeostatic disruptions and its potential as a systemic biomarker.[15]
Liver-Specific Roles and Disease Contexts
Section titled “Liver-Specific Roles and Disease Contexts”The liver is central to the biology of these enzymes, acting as the primary organ responsible for their synthesis and metabolism. Plasma levels of liver enzymes, therefore, often serve as direct indicators of liver health and function. Disturbances in these levels can signal various hepatic disease mechanisms or developmental processes affecting the liver. For instance, specific conditions such as haemochromatosis are known to impact liver function and can be reflected in altered liver enzyme profiles.[16] The monitoring of these enzymes provides crucial insights into organ-specific effects and helps in understanding tissue interactions and compensatory responses within the liver.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Enzymatic Roles in Glutathione Metabolism
Section titled “Enzymatic Roles in Glutathione Metabolism”Glutathione participates in critical metabolic pathways, often through enzymatic conjugation and breakdown, which are essential for maintaining cellular health. The glutathione S-transferase (GST) supergene family plays a significant role in detoxification processes by catalyzing the conjugation of glutathione to various electrophilic compounds, aiding in their removal from the body. [9] These enzymes are central to xenobiotic metabolism, influencing the catabolism of potentially harmful substances and maintaining cellular homeostasis. Similarly, gamma-glutamyltransferase (GGT) is involved in the extracellular degradation of glutathione, an important step in the glutathione-gamma-glutamyl cycle that facilitates amino acid transport and cellular glutathione synthesis.[12] The activity of these enzymes thus represents a key regulatory point in the overall flux and utilization of glutathione within biological systems. [7]
Genetic Regulation and Variability in Glutathione Pathways
Section titled “Genetic Regulation and Variability in Glutathione Pathways”Genetic variations profoundly influence the enzymes involved in glutathione pathways, impacting their expression, activity, and overall functional output. Polymorphisms within the human glutathione S-transferasesupergene family, for instance, are associated with varying susceptibilities to conditions such as lung cancer.[9] Specific genes like GSTM1 through GSTM5, located on human chromosome 1p13, demonstrate this genetic diversity, where different allelic forms can lead to altered enzymatic efficiency or even complete absence of functional protein. [17] Furthermore, serum gamma-glutamyltransferase activity exhibits a substantial genetic influence, suggesting that inherited factors significantly regulate its expression and catalytic rate, which can have downstream effects on metabolic regulation and flux control of glutathione-related processes. [13] These genetic differences constitute a fundamental regulatory mechanism, affecting how individuals process and respond to environmental stressors and endogenous toxins.
Systems-Level Integration and Health Outcomes
Section titled “Systems-Level Integration and Health Outcomes”The enzymes of glutathione metabolism, such as gamma-glutamyltransferase (GGT), are not isolated but operate within complex biological networks, influencing systemic health outcomes. Elevated GGT plasma levels, often indicative of liver enzyme activity, have been linked to long-term survival, suggesting its role as a biomarker for broader physiological resilience or stress. [12] Moreover, studies reveal a genetic covariation between serum GGTactivity and cardiovascular risk factors, highlighting how dysregulation in this pathway can crosstalk with lipid metabolism and inflammation, contributing to complex disease phenotypes.[15]This demonstrates a hierarchical regulation where molecular variations in glutathione-related enzymes can lead to emergent properties at the organismal level, reflecting overall metabolic health and disease susceptibility. Such integrated pathway interactions offer insights into the complex interplay between metabolic regulation and systemic well-being.
Dysregulation and Therapeutic Relevance in Disease
Section titled “Dysregulation and Therapeutic Relevance in Disease”Dysregulation within glutathione-associated pathways significantly contributes to disease pathology, identifying potential therapeutic targets. The polymorphisms within theglutathione S-transferase (GST) supergene family, for instance, are directly associated with an individual’s susceptibility to lung cancer, indicating that variations in detoxification capacity can predispose to malignancy[9]). Similarly, abnormal serum gamma-glutamyltransferase (GGT) activity, often considered a marker of liver function, is genetically linked to cardiovascular risk factors, suggesting its involvement in the pathogenesis of heart disease.[15]These instances of pathway dysregulation highlight how understanding the molecular mechanisms and genetic predispositions in glutathione metabolism can inform strategies for early detection, risk assessment, and the development of targeted interventions to mitigate disease progression. Compensatory mechanisms might also arise in response to such dysregulation, though not explicitly detailed, implying a dynamic biological response to maintain cellular function.
Clinical Relevance
Section titled “Clinical Relevance”Genetic Modulation of Glutathione-Dependent Detoxification
Section titled “Genetic Modulation of Glutathione-Dependent Detoxification”Genetic variations in genes encoding Glutathione S-Transferase (GST) enzymes are critical for understanding the clinical relevance of reduced glutathione, as these enzymes directly utilize reduced glutathione in cellular detoxification processes.[8] The GST superfamily plays a crucial role in metabolizing xenobiotics, including environmental toxins like those found in cigarette smoke. [8] For instance, studies have investigated the influence of GSTP1 and GSTM1on chronic obstructive pulmonary disease (COPD) with some reporting null findings, yet other research indicates that deletions inGSTT1, alone or in combination with GSTM1 deletions, can impact the annual rate of change in lung function within population-based cohorts. [8]These findings highlight that genetic predispositions in glutathione-related pathways may modulate an individual’s response to environmental stressors, thereby influencing disease progression and potentially offering insights into long-term health implications. However, the ultimate validation of such genetic associations requires replication in additional cohorts and further functional studies to establish causality.[4]
Gamma-Glutamyl Transferase: A Biomarker of Glutathione Turnover and Disease Risk
Section titled “Gamma-Glutamyl Transferase: A Biomarker of Glutathione Turnover and Disease Risk”Gamma-glutamyl transferase (GGT), an enzyme central to the extracellular breakdown of glutathione, holds significant clinical relevance for understanding glutathione homeostasis and associated health risks. [7] Plasma levels of GGT exhibit a substantial genetic influence, with genome-wide association studies identifying specific genetic loci that significantly modulate GGT concentrations. [7]Elevated GGT levels are consistently associated with an increased risk of developing common comorbidities such as diabetes and cardiovascular disease, and are predictive of long-term survival.[7] These associations suggest that GGT, as a measurable proxy for aspects of glutathione turnover, can serve as a valuable diagnostic and prognostic tool, aiding in risk assessment and monitoring strategies for these major conditions.
Personalized Risk Assessment and Monitoring in Glutathione-Related Pathways
Section titled “Personalized Risk Assessment and Monitoring in Glutathione-Related Pathways”Understanding the genetic determinants within glutathione-related pathways, such as variations in GST genes and the genetic control of GGT levels, is pivotal for personalized medicine approaches and risk stratification. Identifying specific GSTgenotypes can help pinpoint individuals who may be at higher risk due to compromised detoxification capacities when exposed to environmental toxins, thereby guiding personalized prevention strategies or lifestyle modifications.[8]Similarly, the genetic insights into GGT levels and their strong associations with diabetes and cardiovascular disease can refine individual risk assessments, allowing for more targeted monitoring and early intervention strategies to prevent or manage these conditions.[7]The integration of these genetic and biomarker insights offers a more individualized approach to patient care, moving towards predicting outcomes, assessing disease progression, and tailoring treatment and prevention plans based on an individual’s unique glutathione metabolism profile.
References
Section titled “References”[1] Lu, Shelly C. “Glutathione: metabolism and therapeutic roles in disease.”Antioxidants & Redox Signaling, vol. 15, no. 5, 2011, pp. 1431-1442.
[2] Hayes, John D., et al. “Glutathione and glutathione transferases in health and disease.”Antioxidants & Redox Signaling, vol. 15, no. 6, 2011, pp. 1541-1600.
[3] Wu, Guoyao, et al. “The glutathione system: a multi-functional regulator of cellular redox homeostasis.” Biological Chemistry, vol. 397, no. 1, 2016, pp. 1-13.
[4] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, suppl. 1, 2007, p. S11.
[5] Melzer, D., et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genet, vol. 4, no. 5, 2008, e1000072.
[6] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet, vol. 5, no. 1, 2009, e1000282.
[7] 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. 4, 2008, pp. 520–528.
[8] Wilk, J. B., et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Medical Genetics, vol. 8, 2007.
[9] Ketterer, B., et al. “The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer.”Environ Health Perspect, vol. 98, 1992, pp. 87-94.
[10] Hwang, S. J., et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, S10.
[11] McCarthy, Mark I., et al. “Genome-wide association studies for complex traits: consensus, uncertainty and challenges.” Nature Reviews Genetics, vol. 9, no. 5, 2008, pp. 356-369.
[12] Kazemi-Shirazi, L., et al. “Gamma glutamyltransferase and long-term survival: Is it just the liver?” Clin. Chem., vol. 53, 2007.
[13] Bathum, L., et al. “Evidence for a substantial genetic influence on biochemical liver function tests: Results from a population-based Danish twin study.” Clin. Chem., vol. 47, 2001, pp. 81–87.
[14] Bardini, G., et al. (2008). Liver enzymes and risk of diabetes and cardiovascular disease: Results of the Firenze Bagno a Ripoli (FIBAR) study. Metabolism 57, 387–392.
[15] Whitfield, J.B., et al. “Genetic covariation between serum gamma-glutamyltransferase activity and cardiovascular risk factors.”Clin. Chem., vol. 48, 2002, pp. 1426–1431.
[16] Adams, P.C., and Barton, J.C. (2007). Haemochromatosis. Lancet 370, 1855–1860.
[17] Pearson, W.R., et al. “Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome 1p13.” Am J Hum Genet, vol. 53, 1993, pp. 220–233.