Variability in the fetal hemoglobin level of the normal adult.

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 G γ levels in the Hb F and DNA sequence variations in the locus control region II and in the G γ and A γ promoters. About 25% of the ∼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 ( G γ). One 11-year-old boy was heterozygous for the A→G change at position -161 ( G γ) ; he and two of his relatives had ∼4% Hb F, high G γ values, and a high level of (mainly) G γ-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 ( G γ), and a few carried a γ-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 ( G γ), including factors not linked to the β-globin region, may cause an increase in γ-chain synthesis.