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Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea

Abstract

The increase in fetal hemoglobin (HbF) in response to hydroxyurea (HU) varies among patients with sickle cell anemia. Twenty-nine candidate genes within loci previously reported to be linked to HbF level (6q22.3–q23.2, 8q11–q12 and Xp22.2–p22.3), involved in metabolism of HU and related to erythroid progenitor proliferation were studied in 137 sickle cell anemia patients treated with HU. Three-hundred and twenty tagging single nucleotide polymorphisms (SNPs) for genotyping were selected based on HapMap data. Multiple linear regression and the nonlinear regression Random Forest method were used to investigate the association between SNPs and the change in HbF level after 2 years of treatment with HU. Both methods revealed that SNPs in genes within the 6q22.3–23.2 and 8q11–q12 linkage peaks, and also the ARG2, FLT1, HAO2 and NOS1 genes were associated with the HbF response to HU. Polymorphisms in genes regulating HbF expression, HU metabolism and erythroid progenitor proliferation might modulate the patient response to HU.

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Acknowledgements

We thank the investigators of the MSH who obtained blood samples for DNA-based studies and analyzed data from these studies for the study publications cited in the text of this paper. This study was supported by NHLBI Grant HL R01 70735 (MHS).

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Correspondence to M H Steinberg.

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The study sponsor had no involvement in study design, data collection, analysis or interpretation, writing of the paper or the decision to submit the paper for publication.

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Ma, Q., Wyszynski, D., Farrell, J. et al. Fetal hemoglobin in sickle cell anemia: genetic determinants of response to hydroxyurea. Pharmacogenomics J 7, 386–394 (2007). https://doi.org/10.1038/sj.tpj.6500433

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