Molecular and hematological characteristics of two different δ-globin promoter variants, δ−276(A>G) and δ−77(T >C) among Thai, Burmese, and Laotian subjects

TL;DR

This study examines two genetic variants in the δ-globin gene among Thai, Burmese, and Laotian populations and their effects on hemoglobin levels and thalassemia diagnosis.

Contribution

The study identifies a previously undescribed δ−276(A>G) variant and clarifies its non-pathological nature, contrasting it with the pathologic δ−77(T>C) variant.

Findings

The δ−276(A>G) variant is a non-pathological polymorphism with high frequency in the Thai population.

The δ−77(T>C) variant is pathologic, causing decreased or absent Hb A2 levels in heterozygotes and homozygotes.

β-globin gene haplotype analysis suggests different genetic origins for the δ−77(T>C) variant across populations.

Abstract

We described molecular characteristics, phenotypic expression, and genetic origins of known δ−77(T >C) and hitherto undescribed δ−276(A>G) variants in both heterozygotes and homozygotes found in Thai, Burmese, and Laotian subjects.

A family and 19 unrelated subjects with absent or decreased hemoglobin (Hb) A2 levels referred to three thalassemia diagnostic centers in the north, northeast, and south of Thailand were recruited. Hematological parameters were recorded, and Hb analysis was done using capillary electrophoresis. Molecular analysis of globin genes was carried out by PCR-based methods. β-Globin gene haplotype analysis, including seven DNA polymorphic sites, was done using the PCR-RFLP assay, and the results were compared with those described in the Japanese subject.

A proband with Hb E trait and decreased Hb A2 was identified. DNA sequencing of the δ-globin gene revealed a heterozygosity for a hitherto undescribed δ−276(A>G) transition. However, unusually decreased Hb A2 was not observed in her family members with this δ−276(A>G) mutation in both heterozygote and homozygote states. Further screening of this variant in unrelated Thai individuals revealed a high allele frequency of δ−276(A>G) in the Thai population, the data indicating a non-pathological DNA polymorphism. In contrast, many Thai, Burmese, and Laotian subjects were encountered with another δ-globin promoter variant, the δ−77(T >C) mutation in both heterozygote and homozygote. Most of them had normal hematological features, but decreased Hb A2 in heterozygotes and absent Hb A2 in homozygotes. β-Globin gene haplotype analysis points to different origins of this pathologic variant among Thai, Laotian, Burmese, and Japanese populations.

This study described the molecular characteristics and phenotype-genotype correlation of two different δ-globin promoter variants, δ−77(T >C) and δ−276(A>G), found in the Southeast Asian population. Since the level of Hb A2 is useful for the diagnosis of several forms of thalassemia and hemoglobinopathies, the study of the δ-globin gene in areas endemic for thalassemia and hemoglobinopathies should facilitate a prevention and control program of the diseases in the region.

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