Abstract
Background: Thalassaemia is one of the most common genetic blood disorders worldwide. Patients with β-thalassaemia major and HbE/β-thalassaemia are blood transfusion dependent. Foetal haemoglobin or HbF can play a role in disease manifestations in these patients and there is evidence that a homozygous state for XmnI polymorphic site, associated with increased expression of Gγ-gene, may play an important role among other factors in ameliorating the clinical severity of homozygous β-thalassaemia and thalassaemia intermedia. The aim of this review was to provide a comprehensive review of the role of XmnI polymorphic site for increased HbF production in HbE/β and β-thalassaemia patients.
 Methods: Published literatures were reviewed on the allelic frequency of Xmn1 polymorphism and its effect on HbF induction among thalassaemia patients of different countries.
 Results: In all β-thalassaemias, Hb F levels are relatively increased due to the selective survival of the erythroid precursors that synthesize relatively more γ-chains. The expression of HbF level is dominated by three different loci: HBG2: γ -158C>T, BCL11A, and HBS1L-MYB intergenic region. Genetic determinants influencing Hb F response can be within the β-globin complex or trans-acting. The published literature showed that the C>T substitution (rs7482144) at position –158 of the Gγ-globin gene, referred to as the XmnI-Gγ polymorphism, is a common sequence variant in all population groups, present at a frequency of 0.32 to 0.35. It was found in some studies, response to Hydroxyurea (HU) has been shown to be largely associated with the presence of the C>T polymorphism at -158 XmnI site (HBG2:c.- 53-158C>T) upstream of the Gγ-globin gene and HU therapy exerts a 2- to 9- fold increase in γ-mRNA expression in β-thalassaemia patients.
 Conclusion: A number of various study groups around the world suggests that XmnI polymorphism is an important key regulator of disease severity of HbE/β and β-thalassaemia patients.
Highlights
The word “thalassaemia” derived from the Greek words “Thalassa” and “Haema” refers to the disorders associated with defective synthesis of α- or β-globin subunits of haemoglobin (Hb) A (α2β2)
According to Thalassaemia International Federation (TIF), about 23,000 children are born with transfusiondependent β-thalassaemia major each year, while a smaller ill-defined number have the nontransfusion dependent thalassaemia (NTDT), a form of β-thalassaemia intermedia.[22]
According to World Health Organization (WHO), approximately 3% of the carriers of β-thalassaemia and 4% are the carriers of haemoglobin E (HbE) in Bangladeshi population.[23]
Summary
The word “thalassaemia” derived from the Greek words “Thalassa” (sea) and “Haema” (blood) refers to the disorders associated with defective synthesis of α- or β-globin subunits of haemoglobin (Hb) A (α2β2). According to World Health Organization (WHO), approximately 3% of the carriers of β-thalassaemia and 4% are the carriers of haemoglobin E (HbE) in Bangladeshi population.[23] It is highly concerning that with the birth rate of 21.6/1000, it could be estimated that nearly 2500 thalassaemia major cases are added every year in Bangladesh.[24] As, thalassaemia is a hereditary disease, it is only manageable when it is prevented. Foetal haemoglobin or HbF can play a role in disease manifestations in these patients and there is evidence that a homozygous state for XmnI polymorphic site, associated with increased expression of Gγ-gene, may play an important role among other factors in ameliorating the clinical severity of homozygous β-thalassaemia and thalassaemia intermedia. The aim of this review was to provide a comprehensive review of the role of XmnI polymorphic site for increased HbF production in HbE/β and β-thalassaemia patients
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