Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo.

Pubmed ID: 37976448

Pubmed Central ID: PMC10862365

Journal: Blood

Publication Date: Feb. 1, 2024

MeSH Terms: Humans, Blood Donors, Blood Preservation, Hemolysis, Erythrocytes, Metabolomics, Kynurenine, Large Neutral Amino Acid-Transporter 1

Grants: HHSN268201100001C, HHSN268201100001I, R01 HL126130, R01 HL146442, R01 HL161004, R21 HL150032, R01 HL149714, 75N92019D00033, R01 HL148151, RM1 GM131968

Authors: Busch MP, Kleinman S, Moore A, Deng X, Norris PJ, Page GP, Earley EJ, Nemkov T, Key A, Stephenson D, Dzieciatkowska M, Hansen KC, Zimring JC, D'Alessandro A, Erickson C, Stone M, Roubinian N, Lacroix IS, Raife T

Cite As: Nemkov T, Stephenson D, Erickson C, Dzieciatkowska M, Key A, Moore A, Earley EJ, Page GP, Lacroix IS, Stone M, Deng X, Raife T, Kleinman S, Zimring JC, Roubinian N, Hansen KC, Busch MP, Norris PJ, D'Alessandro A. Regulation of kynurenine metabolism by blood donor genetics and biology impacts red cell hemolysis in vitro and in vivo. Blood 2024 Feb 1;143(5):456-472.

Studies:

Abstract

In the field of transfusion medicine, the clinical relevance of the metabolic markers of the red blood cell (RBC) storage lesion is incompletely understood. Here, we performed metabolomics of RBC units from 643 donors enrolled in the Recipient Epidemiology and Donor Evaluation Study, REDS RBC Omics. These units were tested on storage days 10, 23, and 42 for a total of 1929 samples and also characterized for end-of-storage hemolytic propensity after oxidative and osmotic insults. Our results indicate that the metabolic markers of the storage lesion poorly correlated with hemolytic propensity. In contrast, kynurenine was not affected by storage duration and was identified as the top predictor of osmotic fragility. RBC kynurenine levels were affected by donor age and body mass index and were reproducible within the same donor across multiple donations from 2 to 12 months apart. To delve into the genetic underpinnings of kynurenine levels in stored RBCs, we thus tested kynurenine levels in stored RBCs on day 42 from 13 091 donors from the REDS RBC Omics study, a population that was also genotyped for 879 000 single nucleotide polymorphisms. Through a metabolite quantitative trait loci analysis, we identified polymorphisms in SLC7A5, ATXN2, and a series of rate-limiting enzymes (eg, kynurenine monooxygenase, indoleamine 2,3-dioxygenase, and tryptophan dioxygenase) in the kynurenine pathway as critical factors affecting RBC kynurenine levels. By interrogating a donor-recipient linkage vein-to-vein database, we then report that SLC7A5 polymorphisms are also associated with changes in hemoglobin and bilirubin levels, suggestive of in vivo hemolysis in 4470 individuals who were critically ill and receiving single-unit transfusions.