α-Globin mutations and Genetic Variants in γ-globin Promoters are Associated with Unelevated Hemoglobin F Expression of Atypical β0-thalassemia/HbE

Background

Excessive expression of hemoglobin F (HbF) is a characteristic feature and important diagnostic marker of β⁰-thalassemia/HbE disease. However, some patients may exhibit low-HbF levels, leading to misdiagnosis and precluding genetic counseling. The genetic factors influencing these differences in HbF expression in this atypical disease are not completely understood.

Aims

To investigate determinants contributing to the non-elevation of HbF expression in β⁰-thalassemia/HbE disease.

Methods

We studied 231 patients with β⁰-thalassemia/HbE confirmed by DNA analysis; classified them into the low-HbF (n = 62) and high-HbF (n = 169) groups; analyzed hematological parameters and hemoglobin levels in both groups; and characterized mutations in β- and α-globin genes and genetic variants in γ-globin promoters.

Results

Both groups showed similar rates of type β⁰-thalassemia mutations but significantly different proportions of α-globin mutations: approximately 88.7% (95% confidence interval [CI] = 66.8–115.5) and 39.1% (95% CI = 30.2–49.7) in the low- and high-HbF groups, respectively. The results revealed single-nucleotide polymorphisms (SNPs) at -158 (C>T) in the ^Gγ-globin promoters and novel SNPs at the 5′ untranslated region position 25 (G>A) in ^Aγ-globin promoters. The distribution of CC genotypes of the ^Gγ-globin promoter in the low-HbF group was significantly higher than that in the high-HbF group.

Conclusions

Cases with HbE predominance with low-HbF levels and undetectable HbA may not be as conclusive as those with homozygous HbE until DNA analysis is performed. Concomitant inheritance of α-thalassemia is an important inherent factor modifying HbF expression in a typical β⁰-thalassemia/HbE, and SNPs with the CC genotype in the ^Gγ-globin promoter may indicate unelevated HbF expression in patients with this disease.