Multicenter Study of the Molecular Basis of Thalassemia Intermedia in Different Ethnic Populations

Abstract

We studied 325 thalassemia intermedia patients from Iran, India, Pakistan, Thailand, Mauritius and Cyprus to examine factors which influence the phenotype. The β-thalassemia (thal) mutations were determined for 219 β-thal/β-thal and 106 β-thal/Hb E [β26(B8)Glu→Lys, GAG→AAG] thalassemia intermedia patients. Thirty-one different mutations were identified, and their combination gave rise to more than 44 different genotypes, of which 14 (31.8%) had the β⁰/β⁰, 21 (47.7%) the β⁰/β⁺ and nine (20.5%) the β⁺/β⁺ types. Thus, the β⁺-thal mutations were present in 68.2% of patients.

α-Thalassemia mutations were present in frequencies higher than in the general population of all ethnic groups studied, as 45% of the patients carried α-thal mutations. Correlation of α-thal mutations with β-globin mutations showed that the α-thal mutations were mainly co-inherited with the β⁺-thal mutations.

The XmnI ^Gγ polymorphic site at −158 (C→T) was positive (T) in nine (8.8%) of 102 patients of the β⁺/β⁺ genotype, and the percentage of both XmnI ^Gγ polymorphism [+/−] (T/C) and [+/+] (T/T) genotypes increased to 42.9 and 87.3, respectively, in the β⁰/β⁺ and β⁰/β⁰ patients. This polymorphism was found in the majority of β⁺-thal/Hb E compound heterozygote patients (88.6%), and β⁰-thal/Hb E patients (84.8%), suggesting that it could be linked to the Hb E chromosome. Therefore, the XmnI ^Gγ polymorphism at −158 (C→T) was associated with β⁰-thal mutations as well as the Hb E chromosome.

The present study demonstrates that in cases of thalassemia intermedia with β⁺ mutations, the common ameliorating factor is the presence of α-thal mutations, while in cases with β⁰ mutations, the common ameliorating factor is the presence of the XmnI ^Gγ polymorphism at −158 (C→T).

Keywords:

• Thalassemia intermedia
• Genotype-phenotype correlation
• β-Thalassemia (thal)
• α-Thalassemia (thal)
• XmnI polymorphism at −158 (C→T)
• Cyprus
• Mauritius
• India
• Iran
• Thailand
• Pakistan