Fetal hemoglobin in sickle cell anemia: Relation to regulatory sequences cis to the β-globin gene

Very different fetal hemoglobin levels among adult sickle cell anemia patients suggest genetic modulation of γ-globin gene expression. In sickle cell anemia, different fetal hemoglobin levels are associated with distinct β-globin gene haplotypes. Haplotype may be a marker for linked DNA that modulates γ-globin gene expression. From 295 individuals with sickle cell anemia, we chose for detailed studies 53 patients who had the highest or the lowest fetal hemoglobin levels and 7 patients whose fetal hemoglobin levels were atypical of their haplotype. In these individuals, we examined portions of the β-globin gene locus control region hypersensitive sites two and three, an (AT)(x)(T)(y) repeat 5' to the β-globin gene, a 4-bp deletion 5' to the (A)γ(T) gene, promoters of both γ-globin genes, 5' flanking region of the (G)γ-globin gene, and (A)γ-globin gone IVS-II. Of the regions we studied, all polymorphisms were always haplotype-linked and no additional mutations were present. This suggested that variations in these areas are uncommon mechanisms of fetal hemoglobin modulation in sickle cell anemia. Whereas unexamined cis-acting sequences may regulate γ-globin gene transcription, trans, acting factors may play a more important role.