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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Glutathione is an essential component of the endogenous antioxidant defense system. A decline in glutathione redox balance ― the ratio of reduced (GSH) to oxidized (GSSG) glutathione ― suggests oxidative stress and is associated with kidney disease. Despite the importance of GSH/GSSG, the genetic regulation of this trait is not well defined. In this study, we measured kidney concentrations of GSH and GSSG in mice from 30 genetically‐diverse inbred mouse strains. Genetic background caused an approximately three‐fold difference in kidney GSH/GSSG among the most disparate strains. Haplotype association mapping revealed single nucleotide polymorphisms associated with glutathione concentrations and redox balance. We narrowed the number of significant loci by placing emphasis on those located within protein‐coding genes, and we compared these candidate genes to the results of our previous genetic analysis of hepatic GSH/GSSG. 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. To our knowledge, 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 renal redox biochemistry and possibly inform future therapies for kidney disease. Grant Funding Source: Supported by the following NIH grants: GM101723 (R.P.) and AG032333 (D.E.H.).