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Publication
Ancestry of the α-MRE Associated with the 3.7kb α-Thalassemia Deletion in the Portuguese Population
Advisor(s)
Abstract(s)
The α-major regulatory element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of the α-globin gene expression. It is genetically polymorphic and six haplotypes (A to F) have been identified in different populations. The D haplotype was primary described in African populations and is nearly absent in other populations. The aims of this study were to identify the α-MRE haplotype associated with the common 3.7kb α-thalassemia deletion (-α3.7del) in the Portuguese population, and to investigate its ancestry.
We searched for the -α3.7del in 111 selected Portuguese individuals by Gap-PCR. In addition, a DNA fragment containing the α-MRE was amplified by PCR and Sanger sequenced. Statistical analysis was performed using R software.
Fifty individuals have the wild-type α-globin genotype (group I), 34 are heterozygous for the -α3.7del (group II) and 27 are homozygous (group III). Regarding the α-MRE, four haplotypes were found (A to D). The ancestral A haplotype is predominant in all groups. The B haplotype is the second most frequent in groups I and II, whereas in group III haplotype D is the second most prevalent. Concerning genotypes, the α-MRE AA and AB are the most common in group I, while genotype AD is more prevalent in group III. In fact, 71.4% of AD individuals are homozygous for the -α3.7del. Moreover, the distribution of α-MRE haplotypes and genotypes are significantly different between groups with and without the -α3.7del (p<0.001). Furthermore, multiple correspondence analysis revealed that individuals without the -α3.7del are grouped with other European populations, while samples with the -α3.7del are split from these and found to be more closely related to the African population.
This study revealed for the first time an association of a specific α-MRE haplotype with the common -α3.7del in the Portuguese population, and its likely African ancestry. These results may have clinical importance as the D haplotype has an alteration in the consensus sequence for the AP-1/NF-E2 binding site and in vitro experiments showed a decrease in its enhancer activity on α-globin genes.
Description
Abstract publicado em: Medicine (Baltimore). 2023 Mar 31; 102(13): e33154.
Published online 2023 Mar 31. doi: 10.1097/MD.0000000000033154
Keywords
Doenças Genéticas alfa-talassémia Regulação Génica HS-40 Deleção Portugal