Genetic factors affecting clinical severity in beta-thalassemia syndromes

Purpose: Heterogeneity in the clinical manifestation of beta -thalassemic d iseases may occur from the nature of beta -globin gene mutations, alpha -th alassemia gene interaction, or differences in the amount of hemoglobin (Hb) F production. This study was conducted to determine whether these genetic determinant factors can predict phenotypic severity of patients with beta - thalassemia and to assess the relationship between the genotype and phenoty pe of the disease. Materials and Methods: A total of 144 patients with beta -thalassemia were divided into mild (46 patients), intermediate (55 patients), and severe gro ups (43 patients). DNA analysis based on polymerase chain reaction techniqu e was performed to characterize types of beta -thalassemia mutation, intera ction of alpha -thalassemia, and XmnI polymorphism 5' to (G)gamma -globin g ene. Results: Two alleles of mild beta -thalassemia mutation (beta (+)/beta (+)- thalassemia or beta (+)-thalassemia/Hb E) resulted in a mild clinical sympt om whereas two alleles of severe beta -thalassemia mutation (beta degrees/b eta degrees) produced a severe clinical phenotype. Compound heterozygosity for mild and severe alleles of beta -thalassemia (beta degrees/ beta (+)-th alassemia or beta degrees -thalassemia/Hb E) led to variable severity of an emia. Coinheritance of alpha -thalassemia alleviated the severity of beta - thalassemia disease in those patients with at least one allele of the mild beta -thalassemia genotype. DNA polymorphism at position -158 nt 5' to the (G)gamma -globin gene was demonstrated by XmnI restriction enzyme. Homozygo te of the XmnI site, +/+, was found to have a strong linkage with high Hb F levels and high hemoglobin production in two patients who had mild clinica l symptoms. However, some patients who had XmnI site -/- also had mild clin ical symptoms because the XmnI- was found to be associated with beta (+)-th alassemia mutation. Conclusion: Types of beta -thalassemia mutation and coinheritance of alpha -thalassemia in the patient who has at least one allele of the mild beta -t halassemia genotype are predictive for the clinical severity of the disease . However, a mild clinical symptom in some patients with beta degrees/beta (+)-thalassemia or beta degrees -thalassemia/Hb E who do not have a detecta ble alpha -thalassemia haplotype and no linkage with XmnI++ suggests that t here are other confounding factors responsible for the severity differences of the disease.