Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia

The hydroxycarbamide (HC)-inducible small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR) protein has recently been shown to play a pivotal role in HBG induction and erythroid maturation by causing cell apoptosis and G1/S-phase arrest. Our preliminary analysis indicated that HC inducibility is transcriptionally regulated by elements within the SAR1A promoter. This study aimed to assess whether polymorphisms in the SAR1A promoter are associated with differences Hb F levels or HC therapeutic responses among sickle cell disease (SCD) patients. We studied 386 individuals with SCD comprised of 269 adults treated with or without HC and 117 newborns with SCD identified from a newborn screening program. Three previously unknown single nucleotide polymorphisms (SNPs) in the upstream 5′UTR (−809 C>T, −502 G>T and −385 C>A) were significantly associated with the fetal haemoglobin (HbF) response in Hb SS patients treated with HC (P < 0·05). In addition, four SNPs (rs2310991, −809 C>T, −385 C>A and rs4282891) were significantly associated with the change in absolute HbF after 2 years of treatment with HC. These data suggest that variation within SAR1A regulatory elements might contribute to inter-individual differences in regulation of HbF expression and patient responses to HC in SCD.