Selenium-associated BHMT2 and DMGDH loci connect one-carbon metabolism, selenoprotein biology, and red blood cell fragility.

Storage of red blood cells (RBCs) in the blood bank promotes the accumulation of lesions, including metabolic decline, oxidative injury, membrane remodeling, vesiculation, and hemolysis. Genetic and multi-omic studies implicate iron-dependent lipid peroxidation and ferroptosis-like biology in poor RBC storage quality and post-transfusion recovery, highlighting GPX4, a selenium-dependent antioxidant enzyme, as a candidate modifier of stored RBC fragility. Although the genetic and omic determinants of GPX4 heterogeneity in donated RBCs have been explored, inter-donor variability in RBC selenium levels remains untested. To bridge this gap, selenium was measured by inductively coupled plasma mass spectrometry in 637 blood donors and integrated with stored RBC metabolomics, lipidomics, proteomics, extracellular vesicle and mitochondrial DNA markers, hemolysis phenotypes, and genotypes. Selenium showed broad inter-donor variation but minimal association with age, sex, or BMI. Selenium correlated with day-42 RBC multi-omic features, including iron, zinc, metabolites, lipids, proteins, and EV/mtDNA markers, and showed modest associations with osmotic hemolysis and complete blood count hemoglobin levels. Comparison of high- versus low-selenium donors identified differences in selected selenoprotein trajectories, strongest for GPX1. GWAS of selenium identified chromosome 5 loci near BHMT2 and DMGDH, including an intronic BHMT2-region variant and a DMGDH S279P missense variant. In approximately 13,000 donors from the REDS RBC-Omics index cohort, these loci associated with one-carbon metabolites, selenium-related proteins, detectable RBC selenoproteins, and osmotic hemolysis. These data identify selenium as a genetically anchored axis of RBC storage biology linking one-carbon metabolism, selenoprotein/redox pathways, and selected features of erythrocyte fragility.