Amelioration of Sardinian β0 thalassemia by genetic modifiers

Sardinian β-thalassemia patients all are homozygotes for the same null allele in the β-globin gene, but the clinical manifestations are extremely variable in severity. Previous studies have shown that the coinheritance of α-thalassemia or the presence of genetic variants that sustain fetal hemoglobin production has a strong impact on ameliorating the clinical phenotype. Here we evaluate the contribution of variants in the BCL11A, and HBS1L-MYB genes, implicated in the regulation of fetal hemoglobin, and of α-thalassemia coinheritance in 50 thalassemia intermedia and 75 thalassemia major patients. We confirm that α-thalassemia and allele C of single nucleotide polymorphism rs-11886868 in BCL11A were selectively represented in thalassemia intermedia patients. Moreover, allele G at single nucleotide polymorphism rs9389268 in the HBS1L-MYB locus was significantly more frequent in the thalassemia intermedia patients. This trio of genetic factors can account for 75% of the variation differences in phenotype severity.