The genotype selection in thalassemia: from the basic genetic defect to HbF associated polymorphisms

The malaria-protective β-globin polymorphisms (causing sickle-cell anemia and β0-thalassaemia) are canonical examples of human adaptation to infectious disease. Accordingly, geographic distribution of β-thalassemia carriers is related with the distribution of malaria. On the other hand, clinical observations show that increased levels of fetal hemoglobin (HbF) can ameliorate the severity of these disorders. High HbF levels are associated with regulation of the the biological activity of several transcription repressors, including MYB, BCL11A, Oct-1, KLF1, LYAR. Accordingly, a second-level of selection of certain genotypes/phenotypes might be associated with high HbF levels, leading to lower mortality, especially in the absence of a optimal clinical management of the β-thalassemia patients. In a recent paper we studied a polymorphism of the Aγ-globin gene in four families with β0-thalassemia (β0-IVSII-1 and β0-IVSI-1) and expressing unusual high HbF levels, congenital or acquired after rejection of bone marrow transplantation (1). This (G→A) polymorphism is located at position +25 of the Aγ-globin genes, a region belonging to a sequence recognized by DNA-binding protein complexes, including LYAR (Ly-1 antibody reactive clone), a zinc-finger transcription factor previously proposed to be involved in down-regulation of the expression of γ-globin genes in erythroid cells. We demonstrated that the (G→A) polymorphism decreases the efficiency of LYAR/DNA interactions. In a more recent study we report the sequencing of Aγ-globin genes performed on genomic DNA isolated from a total of 75 β-thalassemia patients, including 31 β039/β039, 33 β039/β+IVSI-110, 9 β+IVSI-110/β+IVSI-110, one β0IVSI-1/β+IVSI-6 and one β039/β+IVSI-6. The major conclusions of this study are the following: (a) the Aγ(+25 G->A) polymorphism is associated with Gγ-globin-XmnI polymorphism; (b) the Aγ(+25 G->A) and Gγ-globin-XmnI polymorphisms are linked with β039-globin gene, but not with β+IVSI-110-globin gene. The finding that this and the XmnI polymorphisms are linked to the β039-globin gene suggests that this genetic feature has been selected in populations during a time period in which the probability to survive was not associated with the optimal clinical management, but rather to high HbF production