An A gamma-globin G-> A gene polymorphism associated with beta(0)39 thalassemia globin gene and high fetal hemoglobin production

作者：Breveglieri Giulia; Bianchi Nicoletta; Cosenza Lucia Carmela; Gamberini Maria Rita; Chiavilli Francesco; Zuccato Cristina; Montagner Giulia; Borgatti Monica; Lampronti Ilaria; Finotti Alessia; Gambari Roberto^*

来源：BMC Medical Genetics, 2017, 18(1): 93.

DOI：10.1186/s12881-017-0450-3

• beta-thalassemia
• Fetal hemoglobin
• LYAR
• A gamma-globin gene polymorphism

Background: Increase of the expression of.-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).
Methods: A gamma-globin gene sequencing was performed on genomic DNA isolated from a total of 75 beta-thalassemia patients, including 31 beta(0)39/beta(0)39, 33 beta(0)39/beta(+) IVSI-110, 9 beta(+) IVSI-110/beta(+) IVSI-110, one beta(IVSI)-I-0-1/beta(+) IVSI-6 and one beta(0)39/beta(IVSI)-I-I-6.
Results: 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(0)39-globin gene, but not with the beta+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(0)39/beta(0)39 thalassemia patients.
Conclusions: 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(0)-thalassemia mutations, but not with the beta(+)-thalassemia mutation here studied (i.e. beta(+) IVSI-110) and that this genetic combination has been selected within the population of beta(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(0)39 thalassemia patients with high HbF in erythroid precursor cells.

• 出版日期2017-8-29