The concentration of glutathione in human erythrocytes is a heritable trait

Erve, Thomas J. van ‘t; Wagner, Brett A.; Ryckman, Kelli K.; Raife, Thomas J.; Buettner, Garry R.

doi:10.1016/j.freeradbiomed.2013.08.002

Cited by 96 publications

(73 citation statements)

References 53 publications

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“…Genetic regulation of GSH/GSSG in mice has significant clinical importance. A recently reported study conducted in human subjects provides data suggesting that red blood cell GSH/GSSG may be heritable in humans as well (22), but genetic effects in humans have not been tested in liver and kidney. Findings that support a relationship between genetics and oxidative stress-related phenotypes like GSH/GSSG create remarkable promise for disease treatments.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis of tissue glutathione concentrations and redox balance

Zhou¹,

Harrison²,

Love-Myers³

et al. 2014

Free Radical Biology and Medicine

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Glutathione redox balance ― defined as the ratio GSH/GSSG ― is a critical regulator of cellular redox state, and declines in this ratio are closely associated with oxidative stress and disease. However, little is known about the impact of genetic variation on this trait. Previous mouse studies suggest that tissue GSH/GSSG is regulated by genetic background and is therefore heritable. In this study, we measured glutathione concentrations and GSH/GSSG in liver and kidney of 30 genetically-diverse inbred mouse strains. Genetic background caused an approximately three-fold difference in hepatic and renal GSH/GSSG between the most disparate strains. Haplotype association mapping determined the loci associated with hepatic and renal glutathione phenotypes. We narrowed the number of significant loci by focusing on those located within protein-coding genes, which we now consider to be candidate genes for glutathione homeostasis. No candidate genes were associated with both hepatic and renal GSH/GSSG, suggesting that genetic regulation of GSH/GSSG occurs predominantly in a tissue-specific manner. This is the first quantitative trait loci study to examine the genetic regulation of glutathione concentrations and redox balance in mammals. We identified novel candidate genes that have the potential to redefine our knowledge of redox biochemistry, its regulation, and inform future therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Genetic analysis of tissue glutathione concentrations and redox balance

Zhou¹,

Harrison²,

Love-Myers³

et al. 2014

Free Radical Biology and Medicine

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“…Samples were further processed and used for measurement of ATP, GSH, and GSSG in RBCs as previously described. 10,11 …”

Section: Methodsmentioning

confidence: 99%

The heritability of hemolysis in stored human red blood cells

et al. 2015

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Background The transfusion of red blood cells (RBCs) with maximum therapeutic efficacy is a major goal in transfusion medicine. One of the criteria used in determining stored RBC quality is end of storage hemolysis. Between donors, a wide range of hemolysis is observed under identical storage conditions. Here, a potential mechanism for this wide range is investigated. We hypothesize that the magnitude of hemolysis is a heritable trait. Also, we investigated correlations between hemolysis and RBC metabolites; this will establish pathways influencing hemolysis as future targets for genetic analysis. Study Design and Methods Units of RBCs from identical and non-identical twins were collected and stored under standard conditions for 56 days. Hemolysis, ATP, and total glutathione were measured throughout storage. Non-targeted metabolic analyses were performed on RBCs that had been stored for 28 days. Heritability was determined by comparing values between identical and non-identical twins. Results Hemolysis was found to be heritable (mean >45 %) throughout the storage period. Correlations were observed between hemolysis and metabolites from the amino acid, sugar, and purine metabolism, lipid metabolism and transport, and glycolysis pathways. Three metabolites also exhibited heritability (> 20%). No correlation was found with ATP or total glutathione. Conclusion The susceptibility of RBCs to lysis during storage is partly determined by inheritance. We have also uncovered several pathways that are candidate targets for future genome wide association studies. These findings will aid in the design of better storage solutions and the development of donor screening tools that minimize hemolysis during storage.

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“…As a result, individuals within twin pairs donated at different times of the day and sometimes weeks apart. Zygosity of twin pairs was verified using DNA from white blood cells obtained from leuko-reduction filters as described in detail in [26]. …”

Section: Methodsmentioning

confidence: 99%

“…There are many inborn errors in the metabolism of GSH that can alter its availability in tissues [24, 25]. In earlier work [26], we established the heritability of the elements of the principal intracellular redox buffer in fresh RBCs, i.e. GSSG and GSH.…”

Section: Introductionmentioning

confidence: 99%

Heritability of glutathione and related metabolites in stored red blood cells

Erve

Doskey

Wagner

et al. 2014

Free Radical Biology and Medicine

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Red blood cells (RBCs) collected for transfusion deteriorate during storage. This deterioration is termed the “RBC storage lesion”. There is increasing concern over the safety, therapeutic efficacy, and toxicity of transfusing longer-stored units of blood. The severity of the RBC storage lesion is dependent on storage-time and varies markedly between individuals. Oxidative damage is considered a significant factor in development of the RBC storage lesion. In this study, the variability during storage and heritability of antioxidants and metabolites central to RBC integrity and function were investigated. In a classic twin study, we determined the heritability of glutathione (GSH), glutathione disulfide (GSSG), the status of the GSSG, 2H+/2GSH couple (Ehc) and total glutathione (tGSH) in donated RBCs over 56 days of storage. Intracellular GSH and GSSG concentrations both decrease during storage (median net loss of 0.52 ± 0.63 mM (median ± SD) and 0.032 ± 0.107mM, respectively over 42 days). Taking into account the decline in pH, Ehc became more positive (oxidized) during storage (median net increase of 35 ± 16 mV). In our study population heritability estimates for GSH, GSSG, tGSH, and Ehc measured over 56 days of storage are 79%, 60%, 67%, and, 75% respectively. We conclude that susceptibility of stored RBCs to oxidative injury due to variations in the GSH-redox buffer are highly variable among individual donors and strongly heritable. Identifying the genes that regulate the storage-related changes in this redox buffer could lead to the development of new methods to minimize the RBC storage lesion.

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The concentration of glutathione in human erythrocytes is a heritable trait

Cited by 96 publications

References 53 publications

Genetic analysis of tissue glutathione concentrations and redox balance

Genetic analysis of tissue glutathione concentrations and redox balance

The heritability of hemolysis in stored human red blood cells

Heritability of glutathione and related metabolites in stored red blood cells

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