RGD Reference Report - Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea. - Rat Genome Database

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Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea.

Authors: Green, NS  Ender, KL  Pashankar, F  Driscoll, C  Giardina, PJ  Mullen, CA  Clark, LN  Manwani, D  Crotty, J  Kisselev, S  Neville, KA  Hoppe, C  Barral, S 
Citation: Green NS, etal., PLoS One. 2013;8(2):e55709. doi: 10.1371/journal.pone.0055709. Epub 2013 Feb 7.
RGD ID: 11353860
Pubmed: PMID:23409025   (View Abstract at PubMed)
PMCID: PMC3567082   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0055709   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HBE1Humansickle cell anemia treatmentIAGP DNA:SNP: :rs7130110 (human)RGD 
Hbb-yMousesickle cell anemia treatmentISOHBE1 (Homo sapiens)DNA:SNP: :rs7130110 (human)RGD 
Hbe1Ratsickle cell anemia treatmentISOHBE1 (Homo sapiens)DNA:SNP: :rs7130110 (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hbe1  (hemoglobin subunit epsilon 1)

Genes (Mus musculus)
Hbb-y  (hemoglobin Y, beta-like embryonic chain)

Genes (Homo sapiens)
HBE1  (hemoglobin subunit epsilon 1)


Additional Information