Role of XmnI polymorphism in HbF induction in HbE/β and β-thalassaemia patients

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.

Association of XmnI Polymorphism with Fetal Hemoglobin Level in Sudanese Patients with Sickle Cell Disease

“…The XmnI polymorphism is a common genetic variation that was reported in previous studies to increase HbF level and therefore ameliorate the severity of the sickle cell disease.Our study shows that a polymorphism of the XmnI was found to be associated with higher expression of HbF in sickle cell and sickle cell trait patients. Several studies confirmed the association between XmnI and fetal hemoglobin 10,11 .Appositive association was observed between the HbF level and the presence of Xmn1 site in SS and sickle thalassemia groups Recently, other genetic association studies shown that several single nucleotide polymorphisms, associated with variation in the expression of HbF in sickle cell disease 12 .The XmnI polymorphism is known to influence the γ G gene expression in sickle cell anemia and to increased HbF concentrations when they are under conditions of erythropoietic stress 13 . Study conducted by FarizKahhaleh et.al to assist the Association of Xmn1 polymorphism and consanguineous marriage with fetal hemoglobin in Syrian patients with sickle cell disease they concluded that a strong evidence on the importance of Xmn1 polymorphism and consanguineous marriage, among other factors, in the prediction of clinical severity and hydroxyurea response in SCD patients 14 .…”