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.

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    • "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]. "
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