Genetic and molecular regulation of gamma globin gene expression in patients with sickle cell disease

The variability of clinical severity in sickle cell anemia patients has been attributed in part to fetal hemoglobin (HbF) expression. Hereditary persistence of fetal hemoglobin (HPFH) describes benign disorders that are characterized by increased gamma-globin chain expression often with a reduction or absence of beta-globin chain expression. HPFH can be due to naturally occurring deletions at the 3' end of the beta-globin locus. Variable size deletions that remove delta (HBD) and beta (HBB) globin genes result in HPFH and deltabeta-thalassemia. We examined clinical and hematology data in 28 patients with sickle hemoglobin (HbS)/HPFH. We found HbS/HPFH patients did not have anemia, and had slightly reduced mean corpuscular volume (MCV). Their age, hemoglobin and MCV were found to be correlated with HbF levels. These individuals were asymptomatic when compared to homozygous HbSS patients even with unusually high levels of HbF.;Three major quantitative trait loci (QTL) significantly associated with HbF levels in individuals from different populations have been identified and include polymorphisms in the Ggamma-globin gene (HBG2) promoter, BCL11A, and the HBS1L-MYB intergenic region. We investigated polymorphisms in these QTL in a unique cohort of 20 African American patients with sickle cell anemia expressing HbF levels equal to or greater than 11%. We also found significant associations of HbF in 2 of the 3 major loci, BCL11A (rs766432) (P=0.05), and HBS1L-MYB intergenic region (rs9399137) (P=0.02). A 3 basepair (bp) (TAC) deletion in high linkage disequilibrium with rs9399137 in the HBS1L-MYB intergenic region might also account for high HbF expression. Two QTL influence HbF levels in African Americans with sickle cell anemia but together account for 20% of HbF variance [1]. Therefore to further explore possible causes of high HbF, we sequenced a 14.1 kilobases (kb) DNA fragment between Agamma-globin gene (HBG1) and HBD in 15 high HbF and 15 low HbF patients. The DNA fragment houses the 7.2kb Corfu deletion that is associated with elevated HbF levels in the homozygous state and also contains binding sites for BCL11A. Thirty-eight single nucleotide polymorphisms (SNPs) were present in both groups of patients. Four SNPs had significantly higher major allele frequencies in the high HbF group (P<0.05) suggesting that polymorphisms in this area might contribute to elevated HbF levels in African American sickle cell anemia patients.