Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the beta-globin gene. Multicenter Study of Hydroxyurea

Abstract

Very different fetal hemoglobin levels among adult sickle cell anemia patients suggest genetic modulation of gamma-globin gene expression. In sickle cell anemia, different fetal hemoglobin levels are associated with distinct beta-globin gene haplotypes. Haplotype may be a marker for linked DNA that modulates gamma-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 beta- globin gene locus control region hypersensitive sites two and three, an (AT)x(T)y repeat 5′ to the beta-globin gene, a 4-bp deletion 5 to the A gamma T gene, promoters of both gamma-globin genes, 5′ flanking region of the G gamma-globin gene, and A gamma-globin gene 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 gamma-globin gene transcription, trans-acting factors may play a more important role.

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease

“…In previous work to attempt to explain the diversity of HbF concentrations within a single haplotype, additional polymorphisms in genetic elements linked to the ␤-globin gene were sought. While polymorphisms in various putative regulatory elements were present in sickle cell anemia patients with different HbF levels, they were always linked to a haplotype [11,[31][32][33][34][35]. Sharing identical ␤-globin gene cluster haplotypes, as do most of our patients, does not exclude heterogeneity in functionally important polymorphisms in this gene cluster that may regulate ␥-globin gene expression [36][37][38][39][40][41].…”

“…Patients with the Senegal or Arab-Indian haplotype tend to have the highest levels of G ␥-globin chains and HbF [18,29]. However, HbF levels vary among patients with the same haplotype; some individuals with the "low" HbF Bantu haplotype may have higher HbF levels than patients with the "high" HbF Senegal haplotype [16,30,31]. The numbers of patients we studied were insufficient for us to analyze the effect of ␤-globin gene cluster haplotype on HbF.…”

Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations

“…The complex regulatory environment that modulates the decline in g-globin gene (HBG2, HBG1) expression from its peak during the 2nd trimester of gestation to its nadir in adult life and its steady-state level in adults provides ample opportunity for genetic modulation [11,12]. Both cis-and trans-acting elements have been found to effect HbF concentration and the contribution from epigenetic modulation is just beginning to be explored [15,16]. In this study we apply newly developed-advanced analytical methods to understand the association of SNPs in candidate genes with the phenotype of HbF levels in adults and in children with sickle cell anemia.…”

research paper: Role of the cold shock domain protein A in the transcriptional regulation of HBG expression

“…For each examined putative regulatory transcription site within the HBB cluster, the nucleotide position, the consensus sequences or the polymorphic variants and the corresponding patient genotypes are reported (the described polymorphic nucleotides are underlined). The N or N¢ sequences at position -10623/-10570 of HS2 are as reported elsewhere (Lu & Steinberg, 1996). heterozygous genotype (C/T for SNP rs11886868 and A/G for SNP rs4895441) for all the three siblings, thus excluding involvement of these two loci in the clinical variability of their b-thalassemic conditions ( Fig S2).…”