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A genetic risk score based on BCL11A and HBS1L-MYB variants predicts clinical severity in Brazilian sickle cell
Gabriela S Arcanjo1,2, Alexsandro P Silva1, Madi V Diniz1
1Genetics and Molecular Biology Postgraduate Program, Federal University of Pernambuco, Recife, Pernambuco, Brazil.
Individuals with sickle cell anaemia (SCA) exhibit significant clinical heterogeneity influenced by several factors, especially fetal haemoglobin (HbF) levels. Variations in adult HbF levels are partly explained by the co-inheritance of genetic variants that regulate globin expression. In this study, we investigated the association of BCL11A rs4671393, rs1427407, rs11886868 and HBS1L-MYB rs9399137 polymorphisms with HbF levels and clinical complications in a cohort of 409 adult Brazilian SCA patients. Our findings reveal that variant alleles of all four single-nucleotide polymorphisms (SNPs) were significantly associated with higher HbF levels. Moreover, homozygosity for the major alleles was independently associated with higher risk and cumulative incidence of stroke, avascular necrosis, leg ulcers, priapism and acute chest syndrome. Haplotype analysis with BCL11A variants was also associated with HbF and the patient's phenotype. A genetic risk score (GRS) combining the risk genotypes was significantly associated with lower HbF levels (p < 0.0001) and increased complication risk (p < 0.0001). A model integrating the GRS with clinical variables demonstrated superior discriminatory performance (area under the curve (AUC): 0.72) compared to models based solely on clinical factors. In summary, this study underscores the clinical relevance of HbF-related genetic variants and supports their integration into risk stratification and personalized management strategies for SCA.
Individuals with sickle cell anaemia (SCA) exhibit significant clinical heterogeneity influenced by several factors, especially fetal haemoglobin (HbF) levels. Variations in adult HbF levels are partly explained by the co-inheritance of genetic variants that regulate globin expression. In this study, we investigated the association of BCL11A rs4671393, rs1427407, rs11886868 and HBS1L-MYB rs9399137 polymorphisms with HbF levels and clinical complications in a cohort of 409 adult Brazilian SCA patients. Our findings reveal that variant alleles of all four single-nucleotide polymorphisms (SNPs) were significantly associated with higher HbF levels. Moreover, homozygosity for the major alleles was independently associated with higher risk and cumulative incidence of stroke, avascular necrosis, leg ulcers, priapism and acute chest syndrome. Haplotype analysis with BCL11A variants was also associated with HbF and the patient's phenotype. A genetic risk score (GRS) combining the risk genotypes was significantly associated with lower HbF levels (p < 0.0001) and increased complication risk (p < 0.0001). A model integrating the GRS with clinical variables demonstrated superior discriminatory performance (area under the curve (AUC): 0.72) compared to models based solely on clinical factors. In summary, this study underscores the clinical relevance of HbF-related genetic variants and supports their integration into risk stratification and personalized management strategies for SCA.
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