BackgroundFetal 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 FindingsIn 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/SignificanceThese 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.

Level II-retrospective study.

The degree of fetal hemoglobin (HbF) expression is a major determinant of phenotypic severity of sickle cell disease (SCD). Genetic regulation of HbF production is complex and can vary among ethnic groups. The pediatric sickle cell population at our institution is approximately half Hispanic, nearly all from the Dominican Republic. Hydroxyurea (HU) is the only FDA-approved drug to ameliorate symptoms of SCD. We retrospectively compared baseline and HU-induced %HbF in African American (AA) and Hispanic (H) patients aged 4–21 years with HbSS or HbSβ0Thalassemia. No significant differences were detected in average baseline %HbF between AA (N=48) and H (N=58) patients (p=0.63). In the subset of children taking hydroxyurea who reached maximum tolerated dose (MTD), no differences were found between the ethnic groups in laboratory response to drug, measured by %HbF at MTD (p=0.28), the increase in %HbF (p=0.31) or mean red cell volume (MCV) (p=0.93), or the MTD of HU (p=0.95). Regulation of HbF at baseline and in response to HU are comparable between Hispanics and African Americans at our center. If generalizable, our results support combining these two groups in future clinical and translational analyses focused on HbF and response to HU in this ethnically-mixed patient population.