Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.

TitleWhole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsSheehan, VA, Crosby, JR, Sabo, A, Mortier, NA, Howard, TA, Muzny, DM, Dugan-Perez, S, Aygun, B, Nottage, KA, Boerwinkle, E, Gibbs, RA, Ware, RE, Flanagan, JM
JournalPLoS One
Date Published2014
KeywordsAnemia, Sickle Cell, Child, Cohort Studies, DNA-Binding Proteins, Dose-Response Relationship, Drug, Exome, Fetal Hemoglobin, Genomics, Humans, Hydroxyurea, Maximum Tolerated Dose, Open Reading Frames, Phenotype, Prospective Studies, Sequence Analysis, DNA, Transcription Factors, Treatment Outcome

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.

Alternate JournalPLoS One
PubMed ID25360671
PubMed Central IDPMC4215999
Grant ListR01-HL090941 / HL / NHLBI NIH HHS / United States
U01-HL078787 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54-HGOO3273 / / PHS HHS / United States
R01 HL090941 / HL / NHLBI NIH HHS / United States
U01 HL078787 / HL / NHLBI NIH HHS / United States

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