Sickle cell disease phenotype. Relationship of haplotypes and polymorphisms in the β cluster, BCL11A and HBS1L-MYB. Pilot study

Abstract

Sickle cell disease (SCD), despite being a monogenic disease, presents a highly variable phenotype that essentially depends on the amount of fetal hemoglobin (HbF), constituting the main modulator of the disease. The variation of HbF levels between patients is genetically regulated. HbF determines both the phenotype of the disease and the response to treatment with the main drug used, hydroxyurea. Researchers’ efforts have focused on discovering the genetic factors responsible for its variation; mainly describing the haplotypes of the β cluster and SNPs in three different loci: BCL11A, HBS1L-MYB and the β-globin cluster. Objective: To determine, in a cohort of patients with SCD, the possible relationship between the number of SNPs and haplotypes with higher levels of HbF. A positive association could explain why certain haplotypes, such as Senegal or Arab-Indian, have higher levels. of HbF and less severe disease. Methods: To verify this hypothesis, the characterization of the haplotypes was carried out using the PCR-RFLP technique and the genotyping of three SNPs representative of the three loci with the greatest association with the variation of HbF: XmnI (rs7482144), BCL11A (rs4671393) and HBS1L-MYB (rs9376092). Results: A greater number of SNPs has been reported in the haplotypes related to higher HbF and a lower number in those with less HbF, although only the SNP XmnI (rs7482144) has shown a statistically significant association. Conclusions: A direct relationship between haplotypes and the number of SNPs has been found, reporting that haplotypes with higher levels of HbF and thus a less severe phenotype, had a greater number of SNPs. Thus, the Benín and Bantu haplotypes traditionally associated with poor prognosis are the ones that have shown a lower number of mutated SNPs.