mQTL analysis for lipid hydroperoxides and glutathionylated adducts in REDS RBC Omics donors and diversity outbred mice confirm a strong association between gene-metabolite networks and ferroptosis pathways. Lipid hydroperoxides and glutathione adducts were measured in 643 REDS recalled donors at storage days 10, 23, and 42 (A), showing storage associated declines in glutathionylated lipid hydroperoxides (B), and increases in lipid hydroperoxides (C). mQTL analyses for all these metabolites (9(S)-HpoTre is highlighted; D) mapped on a region coding for SLC01B1, an hepatic eicosanoid transporter. We observed identical results in 525 diversity outbred mice (The Jackson Laboratory) obtained from >46-generation breeding of 8 genetically diverse mice from the collaborative cross (E). Specifically, storage promoted the elevation of lipid hydroperoxides (F-G), and mQTL mapping highlighted regions on chromosomes 1, 7, and 14 coding for the ferrireductase Steap3, Hbb, and for EPHX2/ApoJ/Clusterin, respectively (H-J). (K) mQTL analyses by genetic ancestry in REDS donors further identify a hit on the rate-limiting enzyme of the PPP, G6PD, with the rs1050828 SNP as the top candidate (African variant V68M N126D). A summary model of the metabolic network involving all identified top candidates from the mQTL analysis is shown in (L).

mQTL analysis for lipid hydroperoxides and glutathionylated adducts in REDS RBC Omics donors and diversity outbred mice confirm a strong association between gene-metabolite networks and ferroptosis pathways. Lipid hydroperoxides and glutathione adducts were measured in 643 REDS recalled donors at storage days 10, 23, and 42 (A), showing storage associated declines in glutathionylated lipid hydroperoxides (B), and increases in lipid hydroperoxides (C). mQTL analyses for all these metabolites (9(S)-HpoTre is highlighted; D) mapped on a region coding for SLC01B1, an hepatic eicosanoid transporter. We observed identical results in 525 diversity outbred mice (The Jackson Laboratory) obtained from >46-generation breeding of 8 genetically diverse mice from the collaborative cross (E). Specifically, storage promoted the elevation of lipid hydroperoxides (F-G), and mQTL mapping highlighted regions on chromosomes 1, 7, and 14 coding for the ferrireductase Steap3, Hbb, and for EPHX2/ApoJ/Clusterin, respectively (H-J). (K) mQTL analyses by genetic ancestry in REDS donors further identify a hit on the rate-limiting enzyme of the PPP, G6PD, with the rs1050828 SNP as the top candidate (African variant V68M N126D). A summary model of the metabolic network involving all identified top candidates from the mQTL analysis is shown in (L).

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