Association between BCL11A, HSB1L-MYB, and XmnI γG-158 (C/T) gene polymorphism and hemoglobin F level in Egyptian sickle cell disease patients.

Sickle cell disease (SCD) is a monogenic disease characterized by multisystem morbidity and highly variable clinical course. Inter-individual variability in hemoglobin F (HbF) levels is one of the main modifiers that account for the clinical heterogeneity in SCD. HbF levels are affected by, among other factors, single nucleotide polymorphisms (SNPs) at the BCL11A gene and the HBS1L-MYB intergenic region and Xmn1 gene. Our aim was to investigate HbF-enhancer haplotypes at these loci to obtain a first overview of the genetic situation of SCD patients in Egypt and its impact on the severity of the disease. The study included 100 SCD patients and 100 matched controls. Genotyping of BCL11A (rs1886868 C/T), HBS1L-MYB (rs9389268 A/G) and Xmn1 γG158 (rs7842144 C/T) SNPs showed no statistically significant difference between SCD patients and controls except for the hetero-mutant genotypes of BCL11A which was significantly higher in SCD patients compared with controls. Baseline HbF levels were significantly higher in those with co-inheritance of polymorphic genotypes of BCL11A + HSB1L-MYB and BCL11A + Xmn1. Steady-state HbF levels, used as an indicator of disease severity, were significantly higher in SCD-Sß patients having the polymorphic genotypes of HSB1L-MYB. Fold change of HbF in both patient groups did not differ between those harboring the wild and the polymorphic genotypes of the studied SNPs. In conclusion, BCL11A, HSB1L, and Xmn1 genetic polymorphisms had no positive impact on baseline HbF levels solely but had if coexisted. Discovery of the molecular mechanisms controlling HbF production could provide a more effective strategy for HbF induction.

Genetic Modifiers of Sickle Cell Disease: A Genotype-Phenotype Relationship Study in a Cohort of 82 Children on Mayotte Island.

Sickle cell disease presents a great clinical variability that remains largely misunderstood. New disease protective genetic modifiers acting mainly through an increased Hb F level have recently been described. We studied relations between clinical and hematological phenotypes and known sickle cell disease genetic modifiers in patients from Mayotte Island, a remote French territory located in the Indian Ocean. Eighty-two children with sickle cell disease were enrolled; their median age was 5.9 years (range 1-18). Clinical and hematological features of sickle cell disease were retrospectively collected. Genetic studies included determination of ß-globin genotypes [Hb SS, Hb S-ß(0)-thalassemia (Hb S-ß(0)-thal), Hb S-ß(+)-thal], ß(S)-globin locus haplotype, α-thalassemia (α-thal), and single nucleotide polymorphisms (SNPs) located in quantitative trait loci for Hb F expression (XmnI polymorphism, BCL11A rs4671393 and rs11886868, intergenic region of HBS1L-MYB rs28384513, rs4895441 and rs9399137). Univariate and multivariate analyses were conducted. Twenty-eight percent of the patients had Hb S-ß-thal (eight different mutations in 21 patients), 55.0% had the -α(3.7) (rightward) deletion and 88.0% of the homozygous Hb SS patients were carrying a homozygous Bantu haplotype. In the multivariate model, the prognosis role of the SNP BCL11A rs4671393 was confirmed in the studied population showing a significant association with an elevated Hb F level and with a low hospitalization rate. The -α(3.7) deletion, XmnI polymorphism and intergenic region HBS1L-MYB SNPs were not significantly linked to any clinical criteria of severity. This report, the first to describe the main features of children with sickle cell disease on Mayotte Island, highlights the protective effect of the BCL11A polymorphism in this population.