BCL11A AND HBS1L-MYB GENETIC VARIANTS PREDICT ADVERSE CLINICAL PHENOTYPES IN SICKLE CELL ANEMIA PATIENTS

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. High HbF levels have a significant physiological impact, primarily by reducing the intraerythrocytic concentration and polymerization of HbS. Consequently, elevated HbF levels in SCA are consistently associated with reduced mortality and morbidity, as well as a lower frequency of several clinical complications. Variations in HbF levels have been attributed to the co-inheritance of genetic variants affecting key transcriptional regulators of gamma-globin expression, such as BCL11A and MYB, which may also be implicated in the risk of disease complications. In this study, we investigated the association of BCL11A (rs4671393 G>A, rs1427407 G>T, rs11886868 T>C) and HBS1L-MYB (rs9399137 T>C) polymorphisms with major clinical complications in 409 adult Brazilian SCA patients, followed at a single reference center in Pernambuco (HEMOPE). Genotyping was performed using real-time PCR with TaqMan® probes. Clinical and laboratory data were retrospectively obtained from medical records. The clinical complications evaluated included stroke, avascular necrosis (AVN), leg ulcers (LUs), priapism, and acute chest syndrome (ACS). The control group comprised SCA patients aged ≥ 18 years who had not developed any of the five major complications by the time of study censure. Logistic regression analysis adjusted for age, gender, and vaso-occlusive crises (VOCs) per year revealed that ancestral genotypes (lower HbF genotypes) of BCL11A and HBS1L-MYB polymorphisms were significantly associated with increased risk of multiple SCA complications. Specifically, BCL11A rs4671393 was independently associated with higher risk of stroke (p = 0.020), AVN (p = 0.016), LUs (p = 0.019), priapism (p = 0.045), and ACS (p = 0.015); rs1427407 was independently associated with stroke (p = 0.041), AVN (p = 0.010), LUs (p = 0.003), priapism (p = 0.005), and ACS (p = 0.010); rs11886868 was independently associated with LUs (p = 0.012); and HBS1L-MYB rs9399137 was independently associated with stroke (p = 0.003), AVN (p = 0.010), and LUs (p = 0.014). Kaplan–Meier and Cox proportional hazards regression models, adjusted for age, gender, and VOCs per year, confirmed that carriers of high-risk genotypes had a greater cumulative incidence of these complications over time. A genetic risk score (GRS) was constructed by summing the number of risk alleles across the four SNPs. Logistic regression analysis, adjusted for age and sex, indicated that higher GRS values were significantly associated with an increased likelihood of developing clinical complications (p < 0.001), suggesting that each additional risk allele contributes to a higher probability of experiencing disease-related complications. Our findings reveal strong associations between BCL11A and HBS1L-MYB polymorphisms and major SCA complications in a well-characterized cohort, reinforcing the clinical significance of HbF regulation in SCA management. Collectively, these results highlight the synergistic contribution of HbF-related genetic modulators in predicting adverse clinical phenotypes, thereby enhancing risk stratification in SCA.