title: Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.
abstract: Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA.
authors.affiliation: Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Vivien A
authors.initials: VA
authors.lastname: Sheehan
authors.affiliation: The University of Texas Graduate School of Biomedical Sciences at Houston, Department of Biostatistics, Bioinformatics, and Systems Biology, University of Texas, Houston, Texas, United States of America; Human Genetics Center, University of Texas, Houston, Texas, United States of America.
authors.forename: Jacy R
authors.initials: JR
authors.lastname: Crosby
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Aniko
authors.initials: A
authors.lastname: Sabo
authors.affiliation: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Mortier
authors.affiliation: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Thad A
authors.initials: TA
authors.lastname: Howard
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Shannon
authors.initials: S
authors.lastname: Dugan-Perez
authors.affiliation: Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, New York, United States of America.
authors.forename: Banu
authors.initials: B
authors.lastname: Aygun
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Nottage
authors.affiliation: Human Genetics Center, University of Texas, Houston, Texas, United States of America; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
authors.affiliation: Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Flanagan
mesh_terms: D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D059472:Exome / Q000187:drug effects / Q000235:genetics*; D005319:Fetal Hemoglobin / Q000378:metabolism*; D023281:Genomics; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D020714:Maximum Tolerated Dose; D016366:Open Reading Frames / Q000235:genetics; D010641:Phenotype; D011446:Prospective Studies; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; C104147:SALL2 protein, human; D014157:Transcription Factors; D005319:Fetal Hemoglobin; D006918:Hydroxyurea