Donor genetics, biology, and metabolomics of blood storage

Abstract

It is well known that there is substantial donor-to-donor variability of RBC storage, and that much of the variability is heritable; however, the genetic basis for such variability is unclear. Similar to genetic variation in humans, RBCs from different inbred strains of mice store differently. Using constructed mouse pedigrees between strains, we have identified candidate genes that are associated with both poor RBC storage (as determined by 24-hour post-transfusion RBC recoveries) and with metabolic pathways that correlate with poor storage. Genetic mapping of 24-hour recoveries identified a significant locus spanning a ~149 Mb interval on chromosome 1 (rs13475827 to rs13476300; p = 2.09 × 10 −31 ). Analysis of this region identified 5 candidate genes ( Gli2 , Steap3 , Ccdc93 , Rab3gap1 , Tli ). Steap3 is a functional enzyme in erythroid cells where it is the primary ferrireductase converting Fe 3+ to Fe 2+ , both mitigating oxidative stress as well as allowing transferrin-dependent iron uptake. Metabolomics analysis identified oxidised lipid products that correlate strongly with post-transfusion RBC survival, including the bioactive lipids Leukotriene B4 (r = 0.71, p = 1.7 × 10 −25 ) and Prostaglandin E2 (r = 0.81, p = 2.6 × 10 −37 ). Genetic mapping of the generation of bioactive lipids mapped to same locus on chromosome 1. Ongoing studies will evaluate the extent to which these findings translate to human donor variability.