Effect of hydroxyurea on G gamma chain fetal hemoglobin synthesis by sickle-cell disease patients

Teixeira, Sérgio Henrique; Cortellazzi, Laura C.; Grotto, Helena Zerlotti Wolf

doi:10.1590/s0100-879x2003001000002

Cited by 3 publications

(2 citation statements)

References 18 publications

(15 reference statements)

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“…HbF is the major modulator of the severity of both sickle cell anemia and b thalassemia and considerable effort is being made to develop methods to increase HBG expression for therapeutic purposes (Deng et al 2014;Lettre and Bauer 2016). Although clinical observations suggest that an increase of HBG2 alone has some benefit (Ballas et al 1991;Teixeira et al 2003;Alsultan et al 2014), modification of trans-acting elements that affect both HbF genes might have a greater effect on HbF levels and help force a more pancellular distribution that could be therapeutically important (Sankaran et al 2011;Steinberg et al 2014;Guda et al 2015;Masuda et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression

Shaikho

Farrell

Sebastiani

et al. 2018

Preprint

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Genetic association studies have detected two trans-acting quantitative trait loci (QTL) on chromosomes 2, 6 and one cis-acting QTL on chromosome 11 that were associated with fetal hemoglobin (HbF) levels.In these studies, HbF was expressed as a percentage of total hemoglobin or the number of erythrocytes that contain HbF (F-cells). As the g-globin chains of HbF are encoded by two non-allelic genes (HBG2, HBG1) that are expressed at different levels we used normalized gene expression and genotype data fromThe Genotype-Tissue Expression (GTEx)-project to study the effects of cis-and trans-acting HbF expression or eQTL. This allowed us to examine mRNA expression of HBG2 and HBG1individually. In addition to studying eQTL for globin genes we examined genes co-expressed with HBG1, studied upstream regulators of HBG1 co-expressed genes and performed a correlation analysis between HBG2 and HBG1 and known HbF regulators. Our results suggest differential effect of cis and trans-acting QTL on HBG and HBG1 expression. Trans-acting eQTLs have the same magnitude of effect on the expression of both HBG2 and HBG1 while the sole cis-acting eQTL affected only HBG2. Furthermore, the analysis of upstream regulators and the correlation analysis suggested that BCL2L1 might be a new potential transacting HbF activator. HbF is the major modulator of the phenotype of sickle cell anemia and b thalassemia. Depending on the effect size, modification of trans-acting elements might have a greater impact on HbF levels than cis-acting elements alone.

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Section: Discussionmentioning

confidence: 99%

Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression

Shaikho

Farrell

Sebastiani

et al. 2018

Preprint

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“…Isto ocorre através da sua ação direta sobre os precursores eritróides, reprogramando-os para uma maior produção desse tipo de hemoglobina (14) . O ácido fólico, por sua vez, segundo Teixeira et al (15) tem como objetivo tornar-se substrato para a produção da série vermelha, a qual se encontra aumentada em decorrência da anemia hemolítica, não tendo, portanto, sua ação, interferência quanto à ocorrência de oclusão vascular periférica.…”

Section: Ss Totalunclassified

Manifestações retinianas em pacientes portadores de anemia de células falciformes

Sobrinho¹,

Saraiva²,

Silva³

et al. 2011

Rev. bras.oftalmol.

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Newer Aspects of the Pathophysiology of Sickle Cell Disease Vaso-Occlusion

2009

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Sickle cell disease is an inherited disorder of hemoglobin (Hb) synthesis, caused by a single nucleotide substitution (GTG>GAG) at the sixth codon of the beta-globin gene, leading to the production of a defective form of Hb, Hb S. When deoxygenated, Hb S polymerizes, damaging the sickle erythrocyte and it is this polymerization that is the primary indispensable event in the molecular pathogenesis of sickle cell disease. Hb S polymerization results in a series of cellular alterations in red cell morphology and function that shorten the red cell life span and leads to vascular occlusion. Sickle cell disease vaso-occlusion is now known to constitute a complex multifactorial process characterized by recurrent vaso-occlusion, ischemia-reperfusion injury, and oxidative stress with consequent vascular endothelial cell activation that induces a chronic inflammatory state in sickle cell disease individual and is propagated by elevated levels of circulating inflammatory cytokines. Activation of the endothelium results in the induction of endothelial adhesion molecule expression that mediates red and white cell adhesion to the vessel wall and the formation of heterocellular aggregates, followed by secondary red cell trapping, all of which contribute to reduced blood flow and eventually obstruction of the micro-circulation. Reduced nitric oxide bioavailability, caused principally by its consumption by cell-free Hb, liberated during intravascular hemolysis, contributes to this process by facilitating vasoconstriction and adhesion molecule activity.

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Effect of hydroxyurea on G gamma chain fetal hemoglobin synthesis by sickle-cell disease patients

Cited by 3 publications

References 18 publications

Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression

Cis- and Trans-Acting Expression Quantitative Trait Loci Differentially Regulate Gamma-Globin Gene Expression

Manifestações retinianas em pacientes portadores de anemia de células falciformes

Newer Aspects of the Pathophysiology of Sickle Cell Disease Vaso-Occlusion

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