title: Genetic analysis of tissue glutathione concentrations and redox balance.
abstract: 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 threefold 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 locus 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 and its regulation and inform future therapeutic applications.
authors.affiliation: Department of Foods and Nutrition and University of Georgia, Athens, GA 30602, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Harrison
authors.affiliation: Department of Statistics, University of Georgia, Athens, GA 30602, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Love-Myers
authors.affiliation: Department of Statistics, University of Georgia, Athens, GA 30602, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Foods and Nutrition and University of Georgia, Athens, GA 30602, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Grider
authors.affiliation: Department of Foods and Nutrition and University of Georgia, Athens, GA 30602, USA.
authors.forename: Kathie
authors.initials: K
authors.lastname: Wickwire
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Burgess
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Mateusz A
authors.initials: MA
authors.lastname: Stochelski
authors.affiliation: Department of Foods and Nutrition and University of Georgia, Athens, GA 30602, USA; The Jackson Laboratory, Bar Harbor, ME 04609, USA. Electronic address: rpazdro@uga.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Pazdro
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D005260:Female; D005786:Gene Expression Regulation; D056426:Genetic Loci; D016678:Genome; D019803:Glutathione Disulfide / Q000235:genetics*; D006239:Haplotypes; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D009928:Organ Specificity; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D013045:Species Specificity
chemical_list: D019803:Glutathione Disulfide
keywords: Free radicals; Genetics; Glutathione; Mice; Redox