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Background <p>Sickle cell anemia (SCA) is a condition caused by a mutation in the <i>HBB</i> 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 <i>BCL11A</i> gene and the <i>HBS1L-MYB</i> intergenic region. In this study, we investigated the combined effects of HU therapy, β<sup>S</sup>-globin haplotypes, and SNPs in <i>BCL11A</i> and the <i>HBS1L-MYB</i> intergenic region on HbF levels in a cohort from Western Bahia, Brazil.</p> Methods and results <p>The DNA of 43 individuals with SCA was analyzed for SNPs rs4671393, rs7557939, rs1427407, and rs11886868 (<i>BCL11A</i>), and rs4895441, rs9402686, and rs11759553 (<i>HBS1L-MYB</i>). Individuals receiving HU therapy presented significantly higher HbF levels than untreated individuals (<i>p</i> = 0.028). Factorial ANOVA demonstrated a significant interaction between HU use, β<sup>S</sup> haplotypes, and sex on HbF variability (<i>p</i> &lt; 0.001). Significant associations with HbF levels were observed for rs7557939 in <i>BCL11A</i> under overdominant models in untreated individuals, and for rs11759553, rs4895441, and rs9402686 in the <i>HBS1L-MYB</i> 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; <i>p</i> = 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.</p> Conclusions <p>These findings reinforce the contribution of genetic variants in <i>BCL11A</i> and <i>HBS1L-MYB</i> 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.</p>

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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

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  • 发表日期：

    2026年6月23日

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  • Manoel Ferreira de Magalhães Filho,
  • Ilana Luize Rocha Santana,
  • Pâmela Lourdes Pereira da Silva,
  • Larissa Paola Rodrigues Venancio

摘要

Background

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.

Methods and results

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.

Conclusions

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.