Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

Department of Pediatrics, Columbia University, New York, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2013; 8(2):e55709. DOI: 10.1371/journal.pone.0055709
Source: PubMed


Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin.
In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels.
These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease.

Download full-text


Available from: Catherine Driscoll
  • Source
    • "BCL11A was previously associated with the human genetic variation in HbF levels [6], [7], [9], [24], the regulation of HbF in adult erythroid cells [10], and the amelioration of the SCD phenotype in adult mice models of the disease [11]. In SCD patients, BCL11A has been associated with the baseline levels of fetal hemoglobin [28] and was down-regulated by hydroxyurea treatment in early reticulocytes [29]. In cooperation with BCL11A, the transcription factor SOX6 was also reported to occupy the human beta-globin cluster and play a role in regulating HbF in adult human erythroid cells [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with sickle cell disease (SCD) and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+) sickle cells cultivated ex vivo in serum-free medium. LIN28A over-expression (LIN28A-OE) increased HbF, reduced beta (sickle)-globin, and strongly suppressed all members of the let-7 family of miRNAs. LIN28A-OE did not affect erythroblast differentiation or prevent enucleation, but it significantly reduced or ameliorated the sickling morphologies of the enucleated erythrocytes.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydroxyurea is the sole approved pharmacologic therapy for sickle cell disease (SCD). Higher fetal hemoglobin (HbF) levels diminish de-oxygenated sickle globin polymerization in vitro and clinically reduce the incidence of disease morbidities. Clinical and laboratory effects of hydroxyurea largely result from induction of HbF expression, though to a highly variable extent. Baseline and hydroxyurea-induced HbF expression are both inherited complex traits. In children with SCD, baseline HbF remains the best predictor of drug-induced levels, but accounts for only portion of the induction. A limited number of validated genetic loci are strongly associated with higher baseline HbF levels in SCD. For induced HbF levels, genetic approaches using candidate single nucleotide polymorphisms (SNP) have identified some of these same loci as also associated with induction. However, SNP associations to induced HbF are only partially independent of baseline levels. Additional approaches to understanding the impact of hydroxyurea on HbF and its other therapeutic effects on SCD include pharmaco-kinetic, gene expression and epigenetic analyses in patients and through existing murine models for SCD. Understanding the genetic and other factors underlying the variability in therapeutic effects of hydroxyurea for pediatric SCD is critical for prospectively predicting good responders and for designing other effective therapies.Pediatric Research (2013); doi:10.1038/pr.2013.227.
    Full-text · Article · Nov 2013 · Pediatric Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although hydroxyurea is the only effective agent for the treatment of sickle cell disease, published experience with this drug is limited to treatment of homozygous sickle cell anemia and HbS/β thalassemia. The role of hydroxyurea in the treatment of patients with HbSD-Punjab, a rare hemoglobinopathy with phenotypic expression similar to that of sickle cell anemia is unknown. Over a period of 10 years, we followed 42 patients with HbSD-Punjab, of which 20 presented with severe clinical manifestations (≥3 episodes of VOC and/or ≥2 units of blood transfusion in the previous 12 months). These 20 patients were enrolled for treatment with hydroxyurea at a dose of 10 mg/kg/day and followed prospectively for a period of 24 months. The frequency of VOC decreased significantly and none of them required blood transfusion while receiving hydroxyurea. The HbF, total hemoglobin, MCV, MCH, and MCHC levels increased significantly, whereas HbS, WBC, platelet count, total serum bilirubin, and LDH levels decreased significantly in all the patients. No short-term drug toxicity was observed. This study describes the use of hydroxyurea therapy in patients with HbSD-Punjab. Low dose hydroxyurea (10 mg/kg/day) was found to be effective in reducing the clinical severity in patients with HbSD-Punjab without any short-term toxicity. In view of easy affordability amongst poor patients, widespread acceptability by patients and doctors, the need of infrequent monitoring and its potential effectiveness, low dose hydroxyurea is suitable for treatment of patients with HbSD-Punjab. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    No preview · Article · Aug 2014 · Pediatric Blood & Cancer
Show more