title: Heritability of glutathione and related metabolites in stored red blood cells.
abstract: 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 the 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 ± 0.107 mM, 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 is 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.
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: van 't Erve
authors.affiliation: Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doskey
authors.affiliation: Free Radical and Radiation Biology Program, Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Hess
authors.affiliation: Department of Pediatrics, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Darbro
authors.affiliation: Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kelli K
authors.initials: KK
authors.lastname: Ryckman
authors.affiliation: Department of Pathology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Raife
authors.affiliation: Free Radical and Radiation Biology Program, Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA. Electronic address: garry-buettner@uiowa.edu.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
mesh_terms: D000293:Adolescent; D000328:Adult; D001793:Blood Preservation; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D005978:Glutathione / Q000032:analysis / Q000235:genetics*; D019803:Glutathione Disulfide / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D019655:Quantitative Trait, Heritable; D014429:Twins, Dizygotic / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics*; D055815:Young Adult
chemical_list: D005978:Glutathione; D019803:Glutathione Disulfide
keywords: Erythrocyte; Glutathione; Heritability; Red blood cells; Storage lesion; Transfusion medicine; Twin study
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