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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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Effect of SALL2 variant rs61743453 on HbF response to hydroxyurea.A, Effect of rs61743453 on delta HbF in discovery cohort. B, Effect of rs61743453 on MTD HbF in validation cohort. Variant refers to the Pro840Arg variant; no individuals were homozygous for this change.
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pone-0110740-g002: Effect of SALL2 variant rs61743453 on HbF response to hydroxyurea.A, Effect of rs61743453 on delta HbF in discovery cohort. B, Effect of rs61743453 on MTD HbF in validation cohort. Variant refers to the Pro840Arg variant; no individuals were homozygous for this change.

Mentions: SALL2 is a multi-zinc finger transcription factor implicated in hematopoietic cell maturation and cell cycle arrest [23]. It contains the same conserved 12 amino acid N-terminal motif as BCL11A [24], [25]. This motif has been shown to be essential for binding of the nucleosome remodeling and deacetylase co-repressor complex, or NuRD, which includes the histone deacelylases HDAC1 and HDAC2. Both HDAC1 and HDAC2 have been shown to act as co-repressors of gamma globin [26]. The variant identified here (rs61743453), causes a proline to arginine change at residue 840 and is predicted to bedamaging to protein function. This P840R SALL2 variant was associated with a higher HbF response to hydroxyurea (Figure 2). Further functional studies will help establish the role of SALL2 in HbF induction in the context of hydroxyurea.


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)

Effect of SALL2 variant rs61743453 on HbF response to hydroxyurea.A, Effect of rs61743453 on delta HbF in discovery cohort. B, Effect of rs61743453 on MTD HbF in validation cohort. Variant refers to the Pro840Arg variant; no individuals were homozygous for this change.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110740-g002: Effect of SALL2 variant rs61743453 on HbF response to hydroxyurea.A, Effect of rs61743453 on delta HbF in discovery cohort. B, Effect of rs61743453 on MTD HbF in validation cohort. Variant refers to the Pro840Arg variant; no individuals were homozygous for this change.
Mentions: SALL2 is a multi-zinc finger transcription factor implicated in hematopoietic cell maturation and cell cycle arrest [23]. It contains the same conserved 12 amino acid N-terminal motif as BCL11A [24], [25]. This motif has been shown to be essential for binding of the nucleosome remodeling and deacetylase co-repressor complex, or NuRD, which includes the histone deacelylases HDAC1 and HDAC2. Both HDAC1 and HDAC2 have been shown to act as co-repressors of gamma globin [26]. The variant identified here (rs61743453), causes a proline to arginine change at residue 840 and is predicted to bedamaging to protein function. This P840R SALL2 variant was associated with a higher HbF response to hydroxyurea (Figure 2). Further functional studies will help establish the role of SALL2 in HbF induction in the context of hydroxyurea.

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