Molecular Analysis of γ-Globin Promoters, HS-111 and 3′HS1, in β-thalassemia Intermedia Patients Associated with High Levels of Hb F.

The nucleotide (nt) variations in the promoter region of the γ-globin genes, HS-111 and 3′HS1 regions, were studied in Iranian patients with β-thalassemia intermedia (β-TI), β-thalassemia major (β-TM) and healthy individuals. Of the five nt variations at the 5′ end of the Aγ-globin gene, −369 (C>G), −611 (−T) and −603/604 (GA>AG) were found in all samples, whereas −588 (A>G) and −AAGC at −222 to −225 were found at different frequencies in the studied groups. Therefore, the −369, −611 and −603/604 variations were considered common mutations in this population, and the difference with respect to the −AAGC deletion was not significant. However, the A allele of the −588 variation and [+] allele of the XmnI polymorphism were more frequent in β-TI patients, especially those who had the IVS-II-1(G>A)/IVS-II-1(G>A) genotype. The + allele of XmnI also had complete correlation with the A allele of −588 variation. The HS-111 (−21 A) variation also showed association with β-TI patients who had high levels of Hb F. Bearing in mind that the −588 variation lies within the postulated adult-specific silencer region and that the majority of β-TI patients had allele A, then it can be envisaged that this allele could have a role in altering the repressor function at this region. Therefore, the A allele of −588, [+] allele of XmnI and HS-111 (−21 A) variation are useful genetic markers to differentiate between β-TM and β-TI patients. However, these nt changes alone may not be the only elements raising the level of Hb F, other regulatory and modifying factors also play a role in Hb F production. [ABSTRACT FROM AUTHOR]