The effect of genetic polymorphisms in trans-acting factor genes as modulators of fetal hemoglobin level in sickle cell disease

Sickle Cell Anemia (SCA), one of the most common autosomal recessive hereditary anemia, is caused by a mutation in the β-globin gene (HBB:c.20A>T) on 11p15.5. This gives rise to a variant named HbS (with the ability to polymerize under certain conditions) as opposed to the normal adult HbA. Although being a monogenic disease, the clinical phenotype of SCA is heterogeneous, ranging from relatively mild to severe, due to the modifying effect of both environmental and genetic factors. Of the latter, the level of fetal hemoglobin (HbF) is one of the most important, being itself conditioned by globinic cis-acting elements as well as non-globinic trans-acting factors. To contribute to a better understanding of the non-globinic genetic factors modulating the expression level of HbF in SCA, we genotyped (by PCR-RFLP) 110 SCA patients, for the SNP rs11886868 located in intron 2 of the BCL11A gene (2p16.1). Also, 79 SCA patients were screened for two other SNPs located in the HBS1L-MYB intergenic region on chromosome 6 (rs4895441 and rs6929404). Patients were divided in two groups, one with HbF8%, and the genotypic and allelic frequencies compared between both groups. Regarding to SNP rs11886868 in the BCL11A gene, we found significant differences between genotypic and allelic frequencies distribution and the HbF levels (p=0.0010 and p=0.0013, respectively). In this SCA population, our results revealed a strong association between the allele C of SNP rs11886868 and HbF levels. Concerning SNPs in the HBS1L-MYB intergenic region (rs4895441 and rs6929404), no association was found with HbF levels. The results gathered in this study confirm that genetic polymorphisms in some transacting factor genes can modulate the HbF level in SCD and, consequently, its pathophysiology. This knowledge may give new insights into new therapeutic strategies development for this pathology.Partially funded by FCT: Programa de Financiamento Plurianual do CIGM