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

Background: Excessive expression of hemoglobin F (HbF) is a characteristic feature and important diagnostic marker of β-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 β-thalassemia/HbE disease.

Methods: We studied 231 patients with β-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 β-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 γ-globin promoters and novel SNPs at the 5' untranslated region position 25 (G>A) in γ-globin promoters. The distribution of CC genotypes of the γ-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 β-thalassemia/HbE, and SNPs with the CC genotype in the γ-globin promoter may indicate unelevated HbF expression in patients with this disease.