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

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

doi:10.1371/journal.pone.0055709

Abstract

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.

Highlights

In sickle cell disease, higher fetal hemoglobin (HbF) levels diminish de-oxygenated sickle globin polymerization in vitro [1] and reduce the incidence of disease morbidities in vivo [2,3]
Three genetic loci have been validated as strongly associated with higher HbF in sickle cell disease: the 59 beta globin locus (HBB) [5,6,7,8,9], not the sickle mutation; the BCL11A repressor of HbF [5,6,7,8,10,11]; and the HS1L-MYB intergenic region [5,6,8,12]
Hydroxyurea-induced HbF is a heritable trait [4] that generally correlates with baseline levels [18,19,20]

Summary

Introduction

Higher fetal hemoglobin (HbF) levels diminish de-oxygenated sickle globin polymerization in vitro [1] and reduce the incidence of disease morbidities in vivo [2,3]. Only limited reports have examined relationships between hydroxyurea-induced HbF and specific genetic polymorphisms in adults with sickle cell disease [13,21] and did not explore the recently identified major loci of interest. Genetic determinants for this clinically relevant marker of drug response have not been confirmed in children [17,19]. Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin

Methods

Results

Conclusion