Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

Jison, Maria; Munson, Peter J.; Barb, Jennifer; Suffredini, Anthony F.; Talwar, Shefali; Logun, Carolea; Raghavachari, Nalini; Beigel, John H.; Shelhamer, James H.; Danner, Robert L.; Gladwin, Mark T.

doi:10.1182/blood-2003-08-2760

Cited by 200 publications

(165 citation statements)

References 63 publications

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“…15,[17][18][19]35,[37][38][39] Gene expression of PBMCs from patients with SCD have exhibited associations with iron homeostasis, inflammation, immunity, and the role or T cells, hypoxic response, and PH. 15,19,35 PBMCs comprise lymphocytes and monocytes and, occasionally, nucleated red blood cells.…”

Section: Discussionmentioning

confidence: 99%

Association of circulating transcriptomic profiles with mortality in sickle cell disease

Desai

Lei

Bahroos

et al. 2017

Blood

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• We validated the association of a circulating genome-wide gene expression profile with poor outcomes in 3 cohorts of SCD.• A composite risk score using this genomic biomarker with clinical risk factors exhibited improved prediction than clinical factors alone.Sickle cell disease (SCD) complications are associated with increased morbidity and risk of mortality. We sought to identify a circulating transcriptomic profile predictive of these poor outcomes in SCD. Training and testing cohorts consisting of adult patients with SCD were recruited and prospectively followed. A pathway-based signature derived from grouping peripheral blood mononuclear cell transcriptomes distinguished 2 patient clusters with differences in survival in the training cohort. These findings were validated in a testing cohort in which the association between cluster 1 molecular profiling and mortality remained significant in a fully adjusted model. In a third cohort of West African children with SCD, cluster 1 differentiated SCD severity using a published scoring index. Finally, a risk score composed of assigning weights to cluster 1 profiling, along with established clinical risk factors using tricuspid regurgitation velocity, white blood cell count, history of acute chest syndrome, and hemoglobin levels, demonstrated a higher hazard ratio for mortality in both the training and testing cohorts compared with clinical risk factors or cluster 1 data alone. Circulating transcriptomic profiles are a powerful method to risk-stratify severity of disease and poor outcomes in both children and adults, respectively, with SCD and highlight potential associated molecular pathways. (Blood. 2017;129(22):3009-3016)

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Section: Discussionmentioning

confidence: 99%

Association of circulating transcriptomic profiles with mortality in sickle cell disease

Desai

Lei

Bahroos

et al. 2017

Blood

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“…However, the role of these circulating cells in biomarker discovery and their potential contribution to the pathobiology of SCD and PAH have both been well established (8,10,26,27). Circulating blood cells may carry disease-specific information due to genetics or due to alterations in their local environment.…”

Section: Discussionmentioning

confidence: 99%

“…The top 631 correlated genes with an elevated TRV were next blasted against previously published PAH-specific microarray data (17) and against SCD-specific microarray data (distinguishing cases from African American control subjects [8]). For the latter comparison, a two-gene intersection was identified (vaccinia related kinase 2, proteasome subunit, a type 3).…”

Section: Functional Analysis Of Differentially Regulated Genes and Comentioning

confidence: 99%

“…Patients with SCD bearing the same HbS genetic mutation differ in their susceptibility to PH development (7), implicating modifier genes, single nucleotide polymorphisms (SNPs), and miRNAs that may contribute to this diversity. Prior studies have used gene expression profiles from peripheral blood mononuclear cells (PBMC) to better understand and characterize patients with SCD compared with healthy control subjects or patients with SCD without hydroxyurea treatment (8). Additionally, genomewide association studies (GWAS) have reported significant associations of genetic markers with hemoglobin F level, overall severity in SCD, and other variables (7,9).…”

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confidence: 99%

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A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Desai¹,

Zhou²,

Ahmad

et al. 2012

Am J Respir Crit Care Med

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Rationale: An increased tricuspid regurgitation jet velocity (TRV . 2.5 m/s) and pulmonary hypertension defined by right heart catheterization both independently confer increased mortality in sickle cell disease (SCD). Objectives: We explored the usefulness of peripheral blood mononuclear cell-derived gene signatures as biomarkers for an elevated TRV in SCD. Methods: Twenty-seven patients with SCD underwent echocardiography and peripheral blood mononuclear cell isolation for expression profiling and 112 patients with SCD were genotyped for single-nucleotide polymorphisms. Measurements and Main Results: Genome-wide gene and miRNA expression profiles were correlated against TRV, yielding 631 transcripts and 12 miRNAs. Support vector machine analysis identified a 10-gene signature including GALNT13 (encoding polypeptide N-acetylgalactosaminyltransferase 13) that discriminates patients with and without increased TRV with 100% accuracy. This finding was then validated in a cohort of patients with SCD without (n ¼ 10) and with pulmonary hypertension (n ¼ 10, 90% accuracy). Increased TRV-related miRNAs revealed strong in silico binding predictions of miR-301a to GALNT13 corroborated by microarray analyses demonstrating an inverse correlation between their expression. A genetic association study comparing patients with an elevated (n ¼ 49) versus normal (n ¼ 63) TRV revealed five significant single-nucleotide polymorphisms within GALNT13 (P , 0.005), four trans-acting (P , 2.1 3 10 27) and one cis-acting (P ¼ 0.6 3 10 24 ) expression quantitative trait locus upstream of the adenosine-A2B receptor gene (ADORA2B). Conclusions: These studies validate the clinical usefulness of genomic signatures as potential biomarkers and highlight ADORA2B and GALNT13 as potential candidate genes in SCD-associated elevated TRV.

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“…Um dos fatores que predispõe ao processo hemolítico das células falciformes, induzindo-o as múltiplas consequências patológicas da DF, deve-se a degradação oxidativa da HbS (Steinberg, 1998;Jison et al, 2004). A desoxigenação da HbS favorece a sua meta-hemoglobinização (meta-Hb S) e a consequente elevação desse pigmento dentro da hemácia.…”

Section: Anemia Falciforme Estresse Oxidativo E Alterações Lipídicasunclassified

Estudo das paraoxonases 1, 2 e 3 em pacientes portadores de anemia falciforme"

Macedo¹

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Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

Cited by 200 publications

References 63 publications

Association of circulating transcriptomic profiles with mortality in sickle cell disease

Association of circulating transcriptomic profiles with mortality in sickle cell disease

A Novel Molecular Signature for Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease

Estudo das paraoxonases 1, 2 e 3 em pacientes portadores de anemia falciforme"

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