BCL11A and HBS1L-MYB polymorphisms, in association with hydroxyurea and sex, modulate fetal hemoglobin levels in individuals with sickle cell anemia in the western region of Bahia, Brazil.

Sickle cell anemia (SCA) is a condition caused by a mutation in the HBB gene, leading to the production of hemoglobin S in red blood cells. Hydroxyurea (HU), used in treatment, increases fetal hemoglobin (HbF) levels, thereby reducing erythrocyte sickling, as do single-nucleotide polymorphisms (SNPs) in the BCL11A gene and the HBS1L-MYB intergenic region. In this study, we investigated the combined effects of HU therapy, βS-globin haplotypes, and SNPs in BCL11A and the HBS1L-MYB intergenic region on HbF levels in a cohort from Western Bahia, Brazil. The DNA of 43 individuals with SCA was analyzed for SNPs rs4671393, rs7557939, rs1427407, and rs11886868 (BCL11A), and rs4895441, rs9402686, and rs11759553 (HBS1L-MYB). Individuals receiving HU therapy presented significantly higher HbF levels than untreated individuals (p = 0.028). Factorial ANOVA demonstrated a significant interaction between HU use, βS haplotypes, and sex on HbF variability (p < 0.001). Significant associations with HbF levels were observed for rs7557939 in BCL11A under overdominant models in untreated individuals, and for rs11759553, rs4895441, and rs9402686 in the HBS1L-MYB region under dominant and recessive models. Multiple linear regression indicated that HU use, sex, rs1427407, rs7557939, and rs4895441 explained 46.5% of the variability in HbF (R² = 0.465; p = 0.001). Linkage disequilibrium (LD) analyses revealed non-random associations between rs4671393 and rs1427407; and between rs9402686, rs4895441, and rs11759553. The transcription factors GATA-1, SMARCA4, and CBFA2T3, which are essential for regulating hematopoietic cell production and differentiation, were associated with these variants. These findings reinforce the contribution of genetic variants in BCL11A and HBS1L-MYB to HbF modulation in SCA. The identification of genetic markers associated with increased HbF levels may contribute to future strategies for individualized therapeutic monitoring in SCA.