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

Nancy S. Green, Katherine L. Ender, Farzana Pashankar, Catherine Driscoll, Patricia J. Giardina, Craig A. Mullen, Lorraine N. Clark, Deepa G. Manwani, Jennifer Crotty, Sergey Kisselev, Kathleen A. Neville, Carolyn Hoppe, Sandra Barral

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: 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. Methodology/Principal Findings: 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. Conclusions/Significance: 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.

Original languageEnglish (US)
Article numbere55709
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 7 2013

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sickle cell anemia
hydroxyurea
Fetal Hemoglobin
Hydroxyurea
Sickle Cell Anemia
hemoglobin
loci
Pediatrics
Genetic Loci
therapeutics
epsilon-Globins
beta-Globins
Polymorphism
single nucleotide polymorphism
Single Nucleotide Polymorphism
Therapeutics
Nucleotides
Maintenance

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Green, N. S., Ender, K. L., Pashankar, F., Driscoll, C., Giardina, P. J., Mullen, C. A., ... Barral, S. (2013). Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea. PLoS One, 8(2), [e55709]. https://doi.org/10.1371/journal.pone.0055709

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea. / Green, Nancy S.; Ender, Katherine L.; Pashankar, Farzana; Driscoll, Catherine; Giardina, Patricia J.; Mullen, Craig A.; Clark, Lorraine N.; Manwani, Deepa G.; Crotty, Jennifer; Kisselev, Sergey; Neville, Kathleen A.; Hoppe, Carolyn; Barral, Sandra.

In: PLoS One, Vol. 8, No. 2, e55709, 07.02.2013.

Research output: Contribution to journalArticle

Green, NS, Ender, KL, Pashankar, F, Driscoll, C, Giardina, PJ, Mullen, CA, Clark, LN, Manwani, DG, Crotty, J, Kisselev, S, Neville, KA, Hoppe, C & Barral, S 2013, 'Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea', PLoS One, vol. 8, no. 2, e55709. https://doi.org/10.1371/journal.pone.0055709
Green, Nancy S. ; Ender, Katherine L. ; Pashankar, Farzana ; Driscoll, Catherine ; Giardina, Patricia J. ; Mullen, Craig A. ; Clark, Lorraine N. ; Manwani, Deepa G. ; Crotty, Jennifer ; Kisselev, Sergey ; Neville, Kathleen A. ; Hoppe, Carolyn ; Barral, Sandra. / Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea. In: PLoS One. 2013 ; Vol. 8, No. 2.
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abstract = "Background: 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. Methodology/Principal Findings: 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. Conclusions/Significance: 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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