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

Abstract

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.

Keywords:

• β-Thalassemia intermedia (β-TI)
• β-Thalassemia major (β-TM)
• Hb F
• γ-Globin gene
• HS-111
• 3′HS1

ACKNOWLEDGMENTS

We would like to thank the staff at the Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran, for their contribution. We also thank our patients for their collaboration. This investigation was supported by a grant from the Pasteur Institute of Iran (No: 387).

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.