Minireview: Multiomic candidate biomarkers for clinical manifestations of sickle cell severity: Early steps to precision medicine

Goodman, Steven R.; Pace, Betty S.; Hansen, Kirk C.; D’Alessandro, Angelo; Xia, Yang; Daescu, Ovidiu; Glatt, Stephen J.

doi:10.1177/1535370216640150

Cited by 17 publications

(14 citation statements)

References 99 publications

(153 reference statements)

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“…While morbidity and mortality are significant in this population, patients demonstrate substantial phenotypic heterogeneity even in the presence of identical mutant alleles of the β‐globin gene, which could be in part explained by underlying genotypic confounders, such as glucose 6‐phosphate dehydrogenase deficiency . SCD is characterized by persistent episodes of hemolytic anemia and the occurrence of acute vaso‐occlusive crises when the sickling red blood cells (RBCs) clog the fine capillary beds . The cumulative impact of recurring vaso‐occlusive crises progressively damages many organs, including the kidneys, lungs, and brain.…”

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confidence: 99%

Effects of red blood cell (RBC) transfusion on sickle cell disease recipient plasma and RBC metabolism

et al. 2018

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Background Exchange transfusion is a mainstay in the treatment of sickle cell anemia. Sickle cell recipients can be transfused over 10 units per therapy, an intervention that replaces circulating sickle red blood cells (RBCs) with donor RBCs. Storage of RBCs makes the intervention logistically feasible. The average storage duration for units transfused at the Duke University Medical Center is ~two weeks, a time window that should anticipate the accumulation of irreversible storage lesion to the erythrocyte. However, no metabolomics study has been performed to date to investigate the impact of exchange transfusion on recipients’ plasma and red blood cell phenotypes. Study design and Methods Plasma and red blood cells were collected from sickle cell patients before transfusion and within 5h from exchange transfusion with up to 11 units, prior to metabolomics analyses. Results Exchange transfusion significantly decreased plasma levels of markers of systemic hypoxemia like lactate, succinate, sphingosine 1-phosphate and 2-hydroxyglutarate. These metabolites accumulated in transfused RBCs, suggesting that RBCs may act as scavenger/reservoirs. Transfused RBCs displayed higher glycolysis, total adenylate pools and DPG, consistent with increased capacity to deliver oxygen. Plasma levels of acyl-carnitines and amino acids decreased, while fatty acids and potentially harmful phthalates increased upon exchange transfusion. Conclusion Metabolic phenotypes confirm the benefits of the transfusion therapy in sickle cell recipients and the reversibility of some of the metabolic storage lesion upon transfusion in vivo in two-week-old RBCs. However, results also suggest that potentially harmful plasticizers are transfused.

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confidence: 99%

Effects of red blood cell (RBC) transfusion on sickle cell disease recipient plasma and RBC metabolism

et al. 2018

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“…Metabolomics, the next generation of metabolic biochemistry, is a powerful hypothesis-free approach highlighting the biological imprinting of the diseases. Surprisingly, very few metabolomic studies have been performed in sickle cell disease so far [2,3]. The most documented study, performed by Darghouth et al [4], compared the RBC from 28 adult patients with the HbSS genotype with those of 24 healthy adults (HbAA), using a chromatography-mass spectrometry based untargeted metabolomic method.…”

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confidence: 99%

Metabolomic Profiling of Plasma and Erythrocytes in Sickle Mice Points to Altered Nociceptive Pathways

Dembélé

Mintz

Veyrat-Durebex

et al. 2020

Cells

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Few data-driven metabolomic approaches have been reported in sickle cell disease (SCD) to date. We performed a metabo-lipidomic study on the plasma and red blood cells of a steady-state mouse model carrying the homozygous human hemoglobin SS, compared with AS and AA genotypes. Among the 188 metabolites analyzed by a targeted quantitative metabolomic approach, 153 and 129 metabolites were accurately measured in the plasma and red blood cells, respectively. Unsupervised PCAs (principal component analyses) gave good spontaneous discrimination between HbSS and controls, and supervised OPLS-DAs (orthogonal partial least squares-discriminant analyses) provided highly discriminant models. These models confirmed the well-known deregulation of nitric oxide synthesis in the HbSS genotype, involving arginine deficiency and increased levels of dimethylarginines, ornithine, and polyamines. Other discriminant metabolites were newly evidenced, such as hexoses, alpha-aminoadipate, serotonin, kynurenine, and amino acids, pointing to a glycolytic shift and to the alteration of metabolites known to be involved in nociceptive pathways. Sharp remodeling of lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins was evidenced in red blood cells. Our metabolomic study provides an overview of the metabolic remodeling induced by the sickle genotype in the plasma and red blood cells, revealing a biological fingerprint of altered nitric oxide, bioenergetics and nociceptive pathways.

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“…While SCD is caused by a single-gene mutation on the ß-globin gene on chromosome 11, there is considerable phenotypic diversity, with a few known genetic modifiersfetal hemoglobin (HbF) expression (Bae et al, 2012;Makani et al, 2011b;Mtatiro et al, 2014) and the coinheritance of alpha-thalassemia (Wonkam et al, 2014)-and many yet unknown. Advancements in genomics research could inform personalized therapeutics (Goodman et al, 2016) and contribute to discoveries of novel physiological targets for intervention (Steinberg and Sebastiani, 2012).…”

Section: Introductionmentioning

confidence: 99%

Stakeholder Perspectives on Public Health Genomics Applications for Sickle Cell Disease: A Methodology for a Human Heredity and Health in Africa (H3Africa) Qualitative Research Study

TreadwellMarsha¹,

Makani²,

Ohene-FrempongKwaku³

et al. 2017

OMICS: A Journal of Integrative Biology

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Advances in omics technologies alone are not a guarantee that science will translate to robust responsible innovation that is firmly grounded in societal values. This study aimed to identify best practices for Ethical, Legal, and Social Implications (ELSI) research in Africa that allows for optimal integration of community perspectives into the design and implementation of genomics research. In a large sample of 346 stakeholders in Cameroon, Ghana, and Tanzania (59% women), we used a qualitative study design with a phenomenological approach and conducted 32 group and 74 individual interviews (25% rural). We imported interview recordings into NVivo software for analysis. We created a “concept map” to organize the coded information, with Perspectives on Genomics and Sickle Cell Disease (SCD) Public Health Interventions as the central themes. We found that (1) analyses of major subthemes across and within countries revealed differential knowledge and experiences of SCD, and perspectives on various aspects of research and genomics; (2) we were able to gather empirical data efficiently from urban and rural stakeholders, to study the issues related to sample sharing, consent processes, and return of clinical and genomic study results; (3) the concept of nondirectiveness in modern genetic medicine practice can be challenged by the views of stakeholders in the context of a high-burden disease such as SCD; and (4) linking community views to current and proposed public health interventions could be understood within the context of each specific country. Our work informs future qualitative social science and technology policy research designs on genomics applications in Africa

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Minireview: Multiomic candidate biomarkers for clinical manifestations of sickle cell severity: Early steps to precision medicine

Cited by 17 publications

References 99 publications

Effects of red blood cell (RBC) transfusion on sickle cell disease recipient plasma and RBC metabolism

Effects of red blood cell (RBC) transfusion on sickle cell disease recipient plasma and RBC metabolism

Metabolomic Profiling of Plasma and Erythrocytes in Sickle Mice Points to Altered Nociceptive Pathways

Stakeholder Perspectives on Public Health Genomics Applications for Sickle Cell Disease: A Methodology for a Human Heredity and Health in Africa (H3Africa) Qualitative Research Study

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