An A[gamma]-globin G-A gene polymorphism associated with [beta]039 thalassemia globin gene and high fetal hemoglobin production

Increase of the expression of [gamma]-globin gene and high production of fetal hemoglobin (HbF) in [beta]-thalassemia patients is widely accepted as associated with a milder or even asymptomatic disease. The search for HbF-associated polymorphisms (such as the XmnI, BCL11A and MYB polymorphisms) has recently gained great attention, in order to stratify [beta]-thalassemia patients with respect to expectancy of the first transfusion, need for annual intake of blood, response to HbF inducers (the most studied of which is hydroxyurea). A[gamma]-globin gene sequencing was performed on genomic DNA isolated from a total of 75 [beta]-thalassemia patients, including 31 [beta].sup.039/[beta].sup.039, 33 [beta].sup.039/[beta].sup.+IVSI-110, 9 [beta].sup.+IVSI-110/[beta].sup.+IVSI-110, one [beta].sup.0IVSI-1/[beta].sup.+IVSI-6 and one [beta].sup.039/[beta].sup.+IVSI-6. The results show that the rs368698783 polymorphism is present in [beta]-thalassemia patients in the 5'UTR sequence (+25) of the A[gamma]-globin gene, known to affect the LYAR (human homologue of mouse Ly-1 antibody reactive clone) binding site 5'-GGTTAT-3'. This A[gamma](+25 G->A) polymorphism is associated with the G[gamma]-globin-XmnI polymorphism and both are linked with the [beta].sup.039-globin gene, but not with the [beta].sup.+IVSI-110-globin gene. In agreement with the expectation that this mutation alters the LYAR binding activity, we found that the A[gamma](+25 G->A) and G[gamma]-globin-XmnI polymorphisms are associated with high HbF in erythroid precursor cells isolated from [beta].sup.039/[beta].sup.039 thalassemia patients. As a potential explanation of our findings, we hypothesize that in [beta]-thalassemia the G[gamma]-globin-XmnI/A[gamma]-globin-(G->A) genotype is frequently under genetic linkage with [beta].sup.0-thalassemia mutations, but not with the [beta].sup.+-thalassemia mutation here studied (i.e. [beta].sup.+IVSI-110) and that this genetic combination has been selected within the population of [beta].sup.0-thalassemia patients, due to functional association with high HbF. Here we describe the characterization of the rs368698783 (+25 G->A) polymorphism of the A[gamma]-globin gene associated in [beta].sup.039 thalassemia patients with high HbF in erythroid precursor cells.