Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Abstract

Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and (G)γ globin. A distinctive DNA polymorphism haplotype in the β globin gene cluster (++-++++-), tightly coupled to a C→T substitution at position -158 5' to the cap site of the (G)γ globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated (G)γ globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated (G)γ to (A)γ ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the (G)γ globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle cell gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi β(s) chromosome, may interact with the -158 C→T substitution and influence γ globin gene expression in this population.