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An association between the HS-40 haplotype D and the 3.7 kb 伪-thalassemia deletion (-伪3.7del) was uncovered by a team of investigators from Portugal.¹

In their study, recently reported in Molecular Biology Reports, the co-authors wrote, 鈥淭his study revealed for the first time an association between the HS-40 haplotype D and the common 3.7 kb 伪-thalassemia deletion in the Portuguese population, and its likely African ancestry.鈥�¹

How did the groups differ?

The research team compared 111 Portuguese individuals with and without -伪3.7del and divided them into 3 groups: Group 1 comprised 50 individuals without the -伪3.7del (genotype 伪伪/伪伪); Group 2 included 34 individuals who were heterozygous for the -伪3.7del (genotype -伪3.7/伪伪); and Group 3 had 27 individuals homozygous for the -伪3.7del (genotype -伪3.7/-伪3.7 ).¹

The hematologic phenotypes differed between the groups in that all participants in Group 1 had normal levels of hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin, while all individuals in Group 3 had hypochromia and microcytosis.

Variations in the prevalence of haplotype D 

Using PCR (polymerase chain reaction) followed by Sanger sequencing (also known as the chain termination method) to amplify the HS-40 region, the investigators identified 4 HS-40 haplotypes, A to D.

They found significant differences in the distribution of the haplotypes and genotypes between the groups with and without the -伪3.7del (P<.001 for the difference between those with homozygous -伪3.7del and those without 伪-thalassemia).

Notably, of the 19 alleles with haplotype D, 15 (78.9%) were in individuals in Group 3, with the homozygous -伪3.7del.

In contrast, haplotype A was the most prevalent in all groups, including among those with and without the 伪-thalassemia deletion; haplotype B, the second most common, was also the second most prevalent in carriers of the -伪3.7del and in those without the -伪3.7del. Haplotype C, on the other hand, occurred rarely and was identified only in 3 individuals, all in Group 1 and all with the wild-type 伪-globin genotype.

The 鈥榓ncestry鈥� of 伪-thalassemia

Seven different combinations of HS-40 genotypes were identified: AA, AB, AD, BB, BC, BD, and DD, with haplotype D seen in 3 of them鈥擜D, BD, and DD.

Interestingly, in the absence of any significant differences (P>.05), the investigators concluded that there was no evidence that any of the genotypes influenced hematologic phenotype.

Finally, after uncovering the association between haplotype D and the -伪3.7del in the Portuguese study cohort, the investigators turned their attention to determining the ancestry of 伪-thalassemia in this population. Multiple correspondence analysis grouped Portuguese individuals without 伪-thalassemia with other European populations, while those with the -伪3.7del were found to be more closely related to those from Africa.

Toward a more precise future

While these findings can鈥檛 be translated directly into clinical practice, they may be early steps on the path to better precision medicine for patients with 伪-thalassemia.

鈥淭his work highlights the importance of further studies to know better the consequences of genetic variability on the long-range regulation of 伪-globin genes in humans,鈥� the study authors concluded. 鈥淭he related experiments, carried out in vitro or in transgenic mice, revealed results that suggest clinical consequences, but these have not yet been validated in humans.鈥�¹

Still, an independent consultant not associated with the study sees possible future clinical relevance.

鈥淭hese findings can guide future research to better understand the mechanisms and develop new therapeutic strategies,鈥� James P. Herman, PhD, an assistant professor at the University of Pittsburgh School of Medicine, told 澳门老奇人论坛. 鈥淚ntegrating this genetic information into clinical practice can lead to more precise and effective care for patients with alpha-thalassemia.鈥�

Published: July 30, 2024