A GENETIC RISK SCORE COMBINING BCL11A AND HBS1L-MYB POLYMORPHISMS IS ASSOCIATED WITH FETAL HEMOGLOBIN LEVELS IN PATIENTS WITH SICKLE CELL ANEMIA

Individuals with sickle cell anemia (SCA) exhibit substantial clinical heterogeneity influenced by several factors, including fetal hemoglobin (HbF) levels, a major protective factor in the disease. HbF is produced through the expression of the HBG (gamma-globin) genes during fetal development. Around birth, HBG genes expression is progressively downregulated, leading to HbF silencing in adulthood. However, some SCA patients maintain elevated HbF levels throughout life. Variations in adult HbF levels have been attributed, in part, to the co-inheritance of genetic variants affecting key transcriptional regulators of gamma-globin expression. Here we investigated the association of BCL11A (rs4671393 G>A, rs1427407 G>T, rs11886868 T>C) and HBS1L-MYB (rs9399137 T>C) polymorphisms with HbF levels in 409 adult Brazilian SCA patients, followed at a single reference center in Pernambuco (HEMOPE). Clinical and laboratory data were retrospectively obtained from patients’ medical records. Baseline laboratory parameters were assessed during treatment-free periods for patients who had received clinical interventions, such as hydroxyurea therapy or chronic blood transfusions. Genotyping was performed using real-time PCR with TaqMan® probes, following the manufacturer’s instructions. Our findings reveal that the variant genotypes of rs4671393, rs1427407, rs11886868, and rs9399137 were significantly associated with higher HbF levels. Linear regression models revealed that all minor alleles of the four polymorphisms were associated with increased HbF levels. Among the BCL11A variants, rs1427407 exhibited the strongest effect (p < 0.001) and explained 7.7% of the variance in HbF levels. However, the HBS1L-MYB variant rs9399137 demonstrated the most substantial effect (p < 0.001), accounting for 14.9% of HbF variance, indicating a stronger regulatory influence on HbF levels. A genetic risk score (GRS) was constructed by summing the number of risk alleles (low HbF levels) present across the four SNPs evaluated. A multiple linear regression model including age and gender as covariates was statistically significant (p < 0.001), explaining approximately 11.5% of the variance in HbF levels. The GRS was significantly associated with HbF levels, indicating that a higher GRS was associated with lower HbF levels. These findings suggest that the cumulative effect of risk variants contributes to reduced HbF levels and may increase the risk of clinical complications. BCL11A and HBS1L-MYB polymorphisms are well-established modulators of HbF levels, and the variants analyzed here are located in regulatory regions, which likely explain their influence on HbF expression. The GRS may serve as a valuable tool for risk stratification, potentially guiding early interventions for patients lacking HbF-boosting alleles. Overall, this study underscores the clinical significance of HbF-related genetic variants for personalized management in SCA.