Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes

Sheehan, Vivien A.; Luo, Zhaoyu; Flanagan, Jonathan M.; Howard, Thad A.; Thompson, Bruce; Wang, Winfred C.; Kutlar, Abdullah; Ware, Russell E.

doi:10.1002/ajh.23457

Cited by 76 publications

(59 citation statements)

References 44 publications

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“…The magnitude of these changes was not significantly correlated with the quantum of improvement of the evaluated clinical outcome parameters thereby suggesting the role of other factors. The results confirm that the effects of HU therapy in SCD override the influence of genetic modifiers as observed by Sheehan et al [13].…”

Section: Discussionsupporting

confidence: 91%

“…A study in India did not find any significant influence of a-thal on clinical scores in SCD patients treated with HU [24]. These observational [13].…”

Section: Discussionmentioning

confidence: 81%

“…Haplotypes may be markers for linked DNA that modulate gamma-globin gene expression. A number of other genetic modifiers are known to affect the phenotypic expression of this classic ''monogenic'' disease [13]. There is a high prevalence of hereditary disorders of hemoglobin synthesis in the Arabian Gulf region [14].…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Hydroxyurea Therapy in Bahraini Sickle Cell Disease Patients

Shome

Ajmi

Radhi

et al. 2015

Indian J Hematol Blood Transfus

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Hydroxyurea (HU) is used as a disease-modifying agent in sickle cell disease (SCD). Its beneficial effects have been ascribed to inhibition of the sickling process through increase of fetal hemoglobin (HbF) levels and influence on multiple factors affecting adhesion of erythrocytes to vascular endothelium. The present study investigates the effect of HU in SCD patients who were grouped on the basis of association with α- and β-thalassemia using routine laboratory methods. A retrospective cross-sectional chart-review was done of 51 adult Bahraini SCD patients attending Salmaniya Medical Complex, Bahrain. Four sub-groups of cases were identified: (i) homozygous sickle cell anemia, 24 cases; (ii) SCD with microcytosis, 16 cases; (iii) sickle α-thalassemia, seven cases; and (iv) sickle β thalassemia, four cases. Documented laboratory and clinical data included hemoglobin level (Hb), hematocrit (Hct), red cell indices, hemoglobin fractions, hospital admissions (frequency), number of inpatient-days, pain episodes (frequency) and red cell transfusion requirement (number of units). Pre- and post-treatment data were compared. Hydroxyurea treatment led to highly significant reduction of HbS % and pain crisis episodes in all patient groups. Other changes such as increases of total hemoglobin, Hct and HbF and reduction of hospital admissions, inpatient days and red cell units transfused also occurred but with less consistent levels of significance within patient sub-groups. Treatment with HU is beneficial for all subgroups of Bahraini SCD patients, without or with α- and β-thalassemia interactions.

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Section: Discussionsupporting

confidence: 91%

“…A study in India did not find any significant influence of a-thal on clinical scores in SCD patients treated with HU [24]. These observational [13].…”

Section: Discussionmentioning

confidence: 81%

See 1 more Smart Citation

The Effect of Hydroxyurea Therapy in Bahraini Sickle Cell Disease Patients

Shome

Ajmi

Radhi

et al. 2015

Indian J Hematol Blood Transfus

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“…Some authors have hypothesized that the effect of HU on HbF level could act through HbF- promoting loci like BCL11A [26]. A recent GWAS studies have revealed further sequence variants that could influence the response to HU [27]. However, the precise molecular mode of action of HU, though these genetic variants, remained to be comprehensively determined.…”

Section: Introductionmentioning

confidence: 99%

A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease

Pule

Mowla

Novitzky

et al. 2015

Expert Review of Hematology

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Aims To report on molecular mechanisms of foetal haemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of Sickle Cell Disease (SCD). Study Design Systematic review. Results Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways, that modulate γ-globin expression (cAMP/cGMP; Giα/JNK/Jun; methylation and microRNA). Three main molecular pathways have been reported: 1) Epigenetic modifications, transcriptional events and signalling pathways involved in HU-mediated response, 2) Signalling pathways involving HU-mediated response and 3) Post-transcriptional pathways (regulation by microRNAs). Conclusions The complete picture of HU-mediated mechanisms of HbF production in SCD remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.

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“…5,6 Alpha-thalassemia (a-thalassemia) is present in about one-third of SCA patients and is associated with reduced hemolysis 7 and protection from albuminuria. 8 A polymorphism in BCL11A (rs1427407, minor allele frequency 0.25) leads to higher fetal hemoglobin (HbF) levels, 9 reduced hemolysis, 10 and amelioration of SCA-related complications, 11 although its relationship with sickle cell nephropathy is unknown.…”

mentioning

confidence: 99%