Increased HbF in sickle cell anemia is determined by a factor linked to the beta S gene from one parent

Abstract

Members of 7 large families, containing 20 patients with sickle cell anemia (SS) characterized by high levels of fetal hemoglobin (HbF), were studied using immunofluorescence to count F cells and a radioimmunoassay to measure small amounts of HbF. In five of these families, one of the sickle cell trait (AS) parents had a much higher HbF and F-cell count than the other; in one family, both parents had a marked increase in HbF and F cells; in the remaining family, HbF and F cells were at borderline values in both parents. Seven of 14 AS siblings, but only 1 of 8 normal hemoglobin (AA) siblings, also had HbF and F-cell counts above the “normal” range. It seems that a factor for increased F cells, linked to the beta S gene of one parent, is segregating in these families and is responsible for the greatly increased HbF and F cells in the SS subjects. HbF per F cell in AS parents and siblings was the same as that of normal AA subjects, whereas in the SS offspring it was greatly increased, suggesting that it was the result of marrow hyperplasia associated with their hemolytic anemia. The similarity of this “increased F-cell gene” to heterocellular hereditary persistence of fetal hemoglobin (HPFH). Swiss type, is discussed, and it is suggested that it may control the persistent synthesis of HbF in sickle cell anemia by its presence in early infancy.

The relative importance of the X‐linked FCP locus and β‐globin haplotypes in determining haemoglobin F levels: a study of SS patients homozygous for βS haplotypes

“…The overall mean % Hb F is quite similar to our study of Jamaican SS patients (7 : 0 Ϯ 5 : 5 versus 6 : 8 Ϯ 4 : 7) (Chang et al, 1995). Female subjects made up 42% of the study group and on average had higher levels of Hb F than males (females 8 : 0 Ϯ 6 : 3; males 6 : 2 Ϯ 4 : 8; P ¼ 0 : 08), as noted in many other studies of SS subjects (Serjeant, 1975;Milner et al, 1984). In this study, 56 individuals were homozygous for the Benin haplotype, 37 were homozygous for the CAR haplotype and 19 were homozygous for the Senegal haplotype.…”

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

“…HbF levels are genetically controlled [15][16][17][20][21][22][23][24]. As siblings with sickle cell disease are likely to share the same ␤-globin genes and their linked regulatory seg-ments, we hypothesized that if some component of the regulation of HbF response to HU is linked to the ␤-globin gene cluster, then siblings might have concordant responses to treatment.…”

Fetal Hemoglobin in Sickle Hemoglobinopathies: High HbF Genotypes and Phenotypes

“…This genotype, the result of many different mutations in the promoters of HBG2 and HBG1 and a single C > T polymorphism in HBG2 , is associated with a diversity of HbF levels ( Table 2 ). The point mutation can be in cis or in trans to the HbS gene [ 27 ]. Once referred to as heterocellular HPFH, HbF can be distributed both pancellularly in cases where HbF levels are high or heterocellularly when HbF is lower, a likely reflection of the level of HBG2 or HBG1 expression [ 4 ].…”