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Publications

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Ppublish 18 citations

PubMed: 37976448 DOI: 10.1182/blood.2023022052

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

Blood 143(5):456-472

Authors: Travis Nemkov, Daniel Stephenson, Christopher Erickson, Monika Dzieciatkowska, Alicia Key, Amy Moore, Eric J Earley, Grier P Page, Ian S Lacroix, Mars Stone, Xutao Deng, Thomas Raife, Steven Kleinman, James C Zimring, Nareg Roubinian, Kirk C Hansen, Michael P Busch, Philip J Norris, Angelo D'Alessandro

Affiliations

  • Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO.
  • Omix Technologies Inc, Aurora, CO.
  • Research Triangle Institute International, Atlanta, GA.
  • Vitalant Research Institute, San Francisco, CA.
  • Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA.
  • Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Department of Pathology, University of British Columbia, Victoria, BC, Canada.
  • Department of Pathology, University of Virginia, Charlottesville, VA.
  • Kaiser Permanente Northern California Division of Research, Oakland, CA.

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.

MeSH

Hematology, Genetics, Blood Donors, Veins, Cells, Hemolysis, Kynurenine

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