Association of Xmn1 −158 γG variant with severity and HbF levels in β-thalassemia major and sickle cell anaemia

Abstract

Haemoglobinopathies including β-thalassemia and sickle cell anaemia (SCA) are considered to be classical monogenic diseases. There is considerable clinical variability between patients inheriting identical β-globin mutations. The reasons for this variability are not well understood. Previous studies have suggested that a variety of genetic determents influence different clinical phenotypes. The genetic variants that modulate HbF levels have a very strong impact on ameliorating the clinical phenotype. In the present study 6,500 blood samples from suspected cases were analysed using HPLC, ARMS-PCR, RDB techniques. Patients with β-thalassemia and SCA were classified into mild, moderate, severe according to the severity score based on Hb levels, age of onset, age at which patients received their first blood transfusion, the degree of growth retardation and splenectomy. Patients with β-thalassemia and SCA were analysed for Xmn1 polymorphism and association between this polymorphism and severity of β-thalassemia and SCA was evaluated. We found a significant difference in genotypic and allelic frequencies of Xmn1 polymorphism between mild and moderate and mild and severe cases. There was a significant difference in high and low percentage of HbF in CC, CT and TT bearing individuals. The TT bearing individuals were found to have a high percentage of HbF in β-thalassemia as well as SCA. This study confirms that increased γG-globin expression associated with Xmn1 polymorphism ameliorates the clinical severity in β-thalassemia as well as SCA in the study population.

The association of HBG2, BCL11A, and HMIP polymorphisms with fetal hemoglobin and clinical phenotype in Iraqi Kurds with sickle cell disease

“…These findings could be explained by the inhibitory effect of HbF on deoxy‐HbS polymerization (which in turn is the major driver of the pathophysiology of this disease) . These observations were to a great extent similar to those reported in Indian SCD patients, where it was found that carriers of the minor allele of rs7482144 had a milder disease with higher hemoglobin and HbF, and lower transfusion and pain crises frequencies . Moreover, Sheehan et al demonstrated that minor alleles at rs1427407 were associated with higher Hb and lower pain frequencies compared to noncarriers.…”

“…35 These observations were to a great extent similar to those reported in Indian SCD patients, where it was found that carriers of the minor allele of rs7482144 had a milder disease with higher hemoglobin and HbF, and lower transfusion and pain crises frequencies. 36,37 Moreover, Sheehan et al 38 demonstrated that minor alleles at rs1427407 were associated with higher Hb and lower pain frequencies compared to noncarriers. While Lettre et al 15 failed to find a significant association between pain episodes frequencies and individual SNP that they studied (including rs7482144 and rs9399137), they did find an inverse correlation between HbF and pain frequency.…”

Modifiers of γ-Globin Gene Expression and Treatment of β-Thalassemia

“…A significant difference in the high and low percentage of HbF in CC, CT, and TT bearing individuals (P<0.01) were observed. This study confirms that increased γG-globin expression, associated with the Xmn1 polymorphism ameliorates the clinical severity in β-thalassemia as well as SCA in the study population [32].…”

Inheritance of IVSI-I Mutation Assures 158 (C-T) XmnI Polymorphism in Thalassemia Intermedia.

“…It has been reported that Gγ-polymorphism increases the production of Hb-F, reducing the severity of the disease. 15,[21][22][23] Thus envisage that presentation of HbS with the support of Xmn-I polymorphism presents in thalassemia intermedia phenotype.…”