Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment

Fertrin, Kleber Yotsumoto; Costa, Fernando Ferreira

doi:10.1586/ehm.10.44

Cited by 76 publications

(58 citation statements)

References 149 publications

(86 reference statements)

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“…It has been recently reported that some degree of focal LV fibrosis measured using late gadolinium enhancement can be seen in young adults with SCA by CMR (42,48), and LV fibrosis was also reported in autopsies of young adults with SCA who died suddenly (77). Moreover, recent reports suggest dysregulated profibrotic pathways are up-regulated in SCA in general, as polymorphisms in TGF-β signaling pathway genes have been found in this patient population (78). We have recently reported hyperangiotensinemia in mice and humans with SCA (79).…”

Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening mentioning

confidence: 52%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.sickle cell anemia | cardiomyopathy | restrictive physiology | arrhythmias | sudden death S ickle cell anemia (SCA) results from a point mutation in the β-globin gene and affects millions world-wide. It is characterized by production of the mutant hemoglobin S (HbS), which polymerizes upon deoxygenation and distorts the shape of RBCs, increasing their propensity to hemolysis and microvascular occlusion. Recurrent cycles of HbS polymerization result in a host of acute and chronic complications, including vaso-occlusive pain crisis, chronic hemolytic anemia, and organ damage. SCA-associated mortality rates have improved because of early diagnosis with universal newborn screening, immunization, and penicillin prophylaxis, which has changed the natural history of SCA (1, 2) and the impact of SCA on organ pathologies is now becoming evident.Despite improved early survival, nearly one-third of young adults with SCA die suddenly (3-9). The sickle myocardium has been presumed to be relatively resistant to the effects of sickling (10), and studies/autopsies show little evidence of atherosclerosis or coronary disease (11)(12)(13)(14). Mildly increased systolic pulmonary arterial pressure (PAP) estimated by tricuspid regurgitant jet vel...

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Section: Berk-ss Mice Develop Corrected Qt Prolongation and Widening mentioning

confidence: 52%

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Bakeer

James

Roy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…There is significant heterogeneity in the rate of development of acute and chronic pain, cerebrovascular disease, acute chest syndrome, 8,9 pulmonary hypertension (PH), diastolic dysfunction, renal failure, hemolytic anemia, and premature or sudden death. [10][11][12][13] Therefore, the development of biomarkers for risk stratification is vital. The utility of such biomarkers in the management of SCD is underscored by their potential application as tools to provide early diagnosis of complications, to identify a subset of individuals at risk for a severe clinical course, to define disease relevant molecular pathways, or to monitor response to therapy.…”

Section: Introductionmentioning

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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“…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).…”

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confidence: 99%

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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Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment

Cited by 76 publications

References 149 publications

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology

Association of circulating transcriptomic profiles with mortality in sickle cell disease

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

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