The recently completed BABY HUG trial investigated the safety and efficacy of
hydroxyurea in infants with
sickle cell anemia (SCA). To investigate the effects of known genetic modifiers, genomic
DNA on 190 randomized subjects were analyzed for
alpha thalassemia,
beta-globin haplotype, polymorphisms affecting endogenous
fetal hemoglobin (HbF) levels (XmnI, BCL11A, and HBS1L-MYB), UGT1A1 promoter polymorphisms, and the common
G6PD A(-) mutation. At study entry, infants with
alpha thalassemia trait had significantly lower mean corpuscular volume, total
bilirubin, and absolute reticulocyte count.
Beta-globin haplotypes associated with milder disease had significantly higher
hemoglobin and %HbF. BCL11A and XmnI polymorphisms had significant effects on baseline HbF, while UGT1A1 promoter polymorphisms significantly influenced baseline serum
bilirubin. At study exit, subjects randomized to placebo still exhibited laboratory effects of
alpha thalassemia and other modifiers, while those assigned
hydroxyurea had treatment effects that exceeded most genetic influences. The
pain phenotype was influenced by HbF modifiers in both treatment groups. These data document that genetic polymorphisms do modify laboratory and clinical phenotypes even in very young patients with SCA. The
hydroxyurea effects are more potent, however, indicating that treatment criteria should not be limited to certain genetic subsets, and supporting the use of
hydroxyurea for all young patients with SCA.