Variability in the fetal hemoglobin level of the normal adult

Abstract

We analyzed blood samples from more than 200 normal adults, and quantified their Hb F by cation-exchange high-performance liquid chromatography. In several subjects with slightly elevated Hb F (0.4-4.3%), we determined the Ggamma levels in the Hb F and DNA sequence variations in the locus control region II and in the Ggamma and Agamma promoters. About 25% of the approximately 200 normal teenaged high school students had elevated Hb F; detailed analyses of some 20 students, selected at random, identified most as females with a homozygosity for the C-->T variation at position -158 (Ggamma). One 11-year-old boy was heterozygous for the A-->G change at position -161 (Ggamma); he and two of his relatives had approximately 4% Hb F, high Ggamma values, and a high level of (mainly) Ggamma-mRNA. Nearly 40 normal adults from Macedonia and from Georgia (mostly Caucasians) were tentatively identified as Swiss HPFH heterozygotes because slightly elevated Hb F levels were observed at least once. Many of these persons were heterozygous or homozygous for the C-->T mutation at -158 (Ggamma), and a few carried a gamma-globin gene triplication. The C-->T change appears to be an important factor predisposing the adult to increased Hb F production. Evidence suggests a gene dose effect in (mildly) anemic adults; however, other factors besides the C-->T change at -158 (Ggamma), including factors not linked to the beta-globin region, may cause an increase in gamma-chain synthesis.

Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

“…Since the T allele is underrepresented in highlanders, it seems not to be advantageous at high altitude. The −158 C→T polymorphism is a modulating factor for the γ-globin gene expression (Tasiopoulou et al, 2007), and the T allele is associated with an increased expression of G γ chains, resulting in an increased HbF level in adults (Sampietro et al, 1992;Leonova et al, 1996;Zertal-Zidani et al, 2002;Tasiopoulou et al, 2007). The T allele did not significantly affect the expression of γ-genes in healthy people, but increases the HbF production under conditions of erythropoietic stress (Thein, 2005).…”

Spectrum of β thalassemia mutations and HbF levels in the heterozygous Moroccan population

“…In the heterozygote, the HbF levels are above 2.5% in the adult, with a dispersion of values up to 14% and are hereditarily transmitted [1,2]. Determinants for this type of hereditary persistence of fetal hemoglobin (HPFH) in normal adults, in ␤ thalassemia and drepanocytosis are multiple and not yet clearly defined [3,4]. Evidence has been provided for the existence of quantitative trait loci influencing F cell number and HbF levels in 6q 22.3-q23.1 [5,6] and at least one other autosomal locus in 8q [7], as well as an F cell production locus in Xp22.2-p22.3 [8,9].…”

Foetal haemoglobin in normal healthy adults: relationship with polymorphic sequences cis to the β globin gene

“…10,11 Some studies have suggested that this cluster is involved in the variability of HbF expression and FC number in individuals with one (heterozygote) or two copies of the b thalassaemic (b thal) or the sickle cell gene, whereas others failed to confirm these findings. 12,13 Studies of sequence variations in the Locus Control Region hypersensitive site-2 (b LCR 5'HS2), 14 ± 16 the second intron of the A g gene (Ag IVS2), 17 the promoter region of the b globin gene 18,19 and the -158 5' of the Gg gene 20,21 have found a genetic association with HbF levels, FC number or both.…”