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

Pharmacogenomics J. 2007 Dec;7(6):386-94. doi: 10.1038/sj.tpj.6500433. Epub 2007 Feb 13.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Anemia, Sickle Cell / blood
  • Anemia, Sickle Cell / drug therapy*
  • Anemia, Sickle Cell / genetics
  • Antisickling Agents / metabolism
  • Antisickling Agents / therapeutic use*
  • Arginase / genetics
  • Biotransformation / genetics
  • Chromosomes, Human, Pair 6
  • Chromosomes, Human, Pair 8
  • Double-Blind Method
  • Erythropoiesis / genetics
  • Fetal Hemoglobin / metabolism*
  • Genotype
  • Humans
  • Hydroxyurea / metabolism
  • Hydroxyurea / therapeutic use*
  • Linkage Disequilibrium
  • Nitric Oxide Synthase Type I / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Severity of Illness Index
  • Time Factors
  • Treatment Outcome
  • United States
  • Vascular Endothelial Growth Factor Receptor-1 / genetics

Substances

  • Antisickling Agents
  • Fetal Hemoglobin
  • Alcohol Oxidoreductases
  • HAO2 protein, human
  • NOS1 protein, human
  • Nitric Oxide Synthase Type I
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1
  • Arginase
  • Hydroxyurea