title: Candidate sequence variants and fetal hemoglobin in children with sickle cell disease treated with hydroxyurea.
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.
  
  
  RESULTS
  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
  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.
authors: Department of Pediatrics, Columbia University, New York, New York, USA. nsg11@columbia.edu
authors: Nancy S
authors: NS
authors: Green
authors: Katherine L
authors: KL
authors: Ender
authors: Farzana
authors: F
authors: Pashankar
authors: Catherine
authors: C
authors: Driscoll
authors: Patricia J
authors: PJ
authors: Giardina
authors: Craig A
authors: CA
authors: Mullen
authors: Lorraine N
authors: LN
authors: Clark
authors: Deepa
authors: D
authors: Manwani
authors: Jennifer
authors: J
authors: Crotty
authors: Sergey
authors: S
authors: Kisselev
authors: Kathleen A
authors: KA
authors: Neville
authors: Carolyn
authors: C
authors: Hoppe
authors: Sandra
authors: S
authors: Barral
mesh_terms: D000293:Adolescent; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000986:Antisickling Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D000986:Antisickling Agents; D005319:Fetal Hemoglobin; D006918:Hydroxyurea