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

Sheehan 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 - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.

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.

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Related in: MedlinePlus

Comparison of discovery and validation cohorts.A, Baseline, or endogenous HbF for the discovery cohort is shown in binned histogram, and distribution of baseline HbF in validation cohort by a line plot. B, Delta HbF for the discovery cohort is shown in binned histogram, and distribution of delta HbF in validation cohort by a line plot. C, Final, or MID HbF for the discovery cohort is shown in binned histogram, and distribution of final, or MID in validation cohort by a line plot.
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pone-0110740-g001: Comparison of discovery and validation cohorts.A, Baseline, or endogenous HbF for the discovery cohort is shown in binned histogram, and distribution of baseline HbF in validation cohort by a line plot. B, Delta HbF for the discovery cohort is shown in binned histogram, and distribution of delta HbF in validation cohort by a line plot. C, Final, or MID HbF for the discovery cohort is shown in binned histogram, and distribution of final, or MID in validation cohort by a line plot.

Mentions: At the time of hydroxyurea initiation, the average age of the 171 patients in the discovery cohort was 10.4±4.5 years of age. The average age of the 130 patients in the validation cohort was 8.1±4.0 years. All patients were treated under a similar dose escalation to MTD regimen according to protocol, or similar institutional guidelines 18, 19. After a minimum of 6 months on hydroxyurea therapy, all patients reached a stable MTD (average 25.1±4.5 mg/kg/day in the discovery cohort, 27.1±4.3 mg/kg/day in the validation cohort) with predictable laboratory benefits (Table 1). The mean increase in HbF was 19.5±6.6% in the discovery cohort and 13.9±7.0% in the validation cohort, reflecting slight differences between the two groups of patients. There was evidence of consistent myelosuppression across both cohorts, however. The baseline HbF, distribution of ΔHbF at MTD and final HbF at MTD were all similar to prior reports (Figure 1, A–C). [15], [20]


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

Sheehan 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 - PLoS ONE (2014)

Comparison of discovery and validation cohorts.A, Baseline, or endogenous HbF for the discovery cohort is shown in binned histogram, and distribution of baseline HbF in validation cohort by a line plot. B, Delta HbF for the discovery cohort is shown in binned histogram, and distribution of delta HbF in validation cohort by a line plot. C, Final, or MID HbF for the discovery cohort is shown in binned histogram, and distribution of final, or MID in validation cohort by a line plot.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215999&req=5

pone-0110740-g001: Comparison of discovery and validation cohorts.A, Baseline, or endogenous HbF for the discovery cohort is shown in binned histogram, and distribution of baseline HbF in validation cohort by a line plot. B, Delta HbF for the discovery cohort is shown in binned histogram, and distribution of delta HbF in validation cohort by a line plot. C, Final, or MID HbF for the discovery cohort is shown in binned histogram, and distribution of final, or MID in validation cohort by a line plot.
Mentions: At the time of hydroxyurea initiation, the average age of the 171 patients in the discovery cohort was 10.4±4.5 years of age. The average age of the 130 patients in the validation cohort was 8.1±4.0 years. All patients were treated under a similar dose escalation to MTD regimen according to protocol, or similar institutional guidelines 18, 19. After a minimum of 6 months on hydroxyurea therapy, all patients reached a stable MTD (average 25.1±4.5 mg/kg/day in the discovery cohort, 27.1±4.3 mg/kg/day in the validation cohort) with predictable laboratory benefits (Table 1). The mean increase in HbF was 19.5±6.6% in the discovery cohort and 13.9±7.0% in the validation cohort, reflecting slight differences between the two groups of patients. There was evidence of consistent myelosuppression across both cohorts, however. The baseline HbF, distribution of ΔHbF at MTD and final HbF at MTD were all similar to prior reports (Figure 1, A–C). [15], [20]

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.

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.

Show MeSH
Related in: MedlinePlus