RESUMO
ABSTRACT: Recent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor. We also measured l-carnitine and acyl-carnitines in 13 091 packed RBC units from donors in the Recipient Epidemiology and Donor Evaluation study. Genome-wide association studies against 879 000 polymorphisms identified critical genetic factors contributing to interdonor heterogeneity in end-of-storage carnitine levels, including common nonsynonymous polymorphisms in genes encoding carnitine transporters (SLC22A16, SLC22A5, and SLC16A9); carnitine synthesis (FLVCR1 and MTDH) and metabolism (CPT1A, CPT2, CRAT, and ACSS2), and carnitine-dependent repair of lipids oxidized by ALOX5. Significant associations between genetic polymorphisms on SLC22 transporters and carnitine pools in stored RBCs were validated in 525 Diversity Outbred mice. Donors carrying 2 alleles of the rs12210538 SLC22A16 single-nucleotide polymorphism exhibited the lowest l-carnitine levels, significant elevations of in vitro hemolysis, and the highest degree of vesiculation, accompanied by increases in lipid peroxidation markers. Separation of RBCs by age, via in vivo biotinylation in mice, and Percoll density gradients of human RBCs, showed age-dependent depletions of l-carnitine and acyl-carnitine pools, accompanied by progressive failure of the reacylation process after chemically induced membrane lipid damage. Supplementation of stored murine RBCs with l-carnitine boosted posttransfusion recovery, suggesting this could represent a viable strategy to improve RBC storage quality.
Assuntos
Carnitina , Eritrócitos , Hemólise , Carnitina/metabolismo , Humanos , Animais , Camundongos , Eritrócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Envelhecimento Eritrocítico , Estudo de Associação Genômica Ampla , Masculino , Feminino , Membro 5 da Família 22 de Carreadores de Soluto/genética , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Preservação de Sangue/métodosRESUMO
BACKGROUND: A linked donor-recipient study was conducted during epidemics in 2 cities in Brazil to investigate transfusion-transmitted (TT) dengue virus (DENV) by DENV RNA-positive donations. METHODS: During February-June 2012, samples were collected from donors and recipients and retrospectively tested for DENV RNA by transcription-mediated amplification. Recipient chart review, using a case (DENV positive)-control (DENV negative and not known to be exposed) design, was conducted to assess symptoms. RESULTS: Of 39 134 recruited blood donors, DENV-4 viremia was confirmed in 0.51% of donations from subjects in Rio de Janeiro and 0.80% of subjects in Recife. Overall, 42 DENV RNA-positive units were transfused into 35 recipients. Of these, 16 RNA-positive units transfused into 16 susceptible recipients were identified as informative: 5 cases were considered probable TT cases, 1 possible TT case, and 10 nontransmissions. The TT rate was 37.5% (95% confidence interval [CI], 15.2%-64.6%), significantly higher than the viremia rate of 0.93% (95% CI, .11%-3.34%) in nonexposed recipients (P < .0001). Chart review did not find significant differences between cases and controls in symptoms or mortality. CONCLUSIONS: During a large epidemic of DENV-4 infection in Brazil, >0.5% of donations were RNA positive, and approximately one third of components resulted in TT. However, no significant clinical differences were evident between RNA-positive and RNA-negative recipients.