Fetal hemoglobin in sickle cell anemia: Molecular characterization of the unusually high fetal hemoglobin phenotype in African Americans

Abstract

Fetal hemoglobin (HbF) is a major modifier of disease severity in sickle cell anemia (SCA). Three major HbF quantitative trait loci (QTL) are known: the Xmn I site upstream of Gγ-globin gene (HBG2) on chromosome 11p15, BCL11A on chromosome 2p16, and HBS1L-MYB intergenic polymorphism (HMIP) on chromosome 6q23. However, the roles of these QTLs in SCA patients with uncharacteristically high HbF are not known. We studied 20 African American SCA patients with markedly elevated HbF (mean 17.2%). They had significantly higher minor allele frequencies (MAF) in two HbF QTLs, BCL11A and HMIP, compared with those with low HbF. A 3-bp (TAC) deletion in complete linkage disequilibrium (LD) with the minor allele of rs9399137 in HMIP was also present significantly more often in these patients. To further explore other genetic loci that might be responsible for this high HbF, we sequenced a 14.1 kb DNA fragment between the Aγ(HBG1) and δ-globin genes (HBD). Thirty-eight SNPs were found. Four SNPs had significantly higher major allele frequencies in the unusually high HbF group. In silico analyses of these 4 polymorphisms predicted alteration in transcription factor binding sites in 3.

Fetal hemoglobin in sickle cell anemia: a glass half full?

“…Some African Americans with sickle cell anemia have HbF levels similar to individuals with the AI haplotype. 18 Like AI haplotype adult patients, their disease is not benign. In contrast to HbS-HPFH, HbF is unevenly distributed among erythrocytes in all of these patient groups.…”

Minireview: Clinical severity in sickle cell disease: the challenges of definition and prognostication

“…HbF expression is also regulated by trans-acting elements (unlinked to the β-globin locus), such as single nucleotide polymorphisms or small deletions within or near the BCL11A gene on chromosome 2p16, the HBS1L-MYB intergenic region on chromosome 6q23, and other genes. 12,13 Regardless of the source of variation, the HbF level clearly modifies the phenotype of HbSS, and increasing concentrations of HbF increasingly ameliorate the disease. Accordingly, induction of high levels of HbF continues to be an attractive therapeutic goal.…”

Genetic modulation of fetal hemoglobin in hydroxyurea‐treated sickle cell anemia

“…Genome-wide association studies (GWAS) have revealed three quantitative trait loci (QTL), HBG2 on chromosome 11p15, HBS1L-MYB ( HMIP ) intergenic region on chromosome 6q23 and BCL11A on chromosome 2p16, which account for 20–50% of HbF variation in sickle cell anemia (SCA). The olfactory receptors genes might have a regulatory role in γ-globin gene expression [1, 2]. …”