Existence of HbF Enhancer Haplotypes at HBS1L-MYB Intergenic Region in Transfusion-Dependent Saudi β-Thalassemia Patients

Abstract

Background and Objectives. β-Thalassemia and sickle cell disease are genetic disorders characterized by reduced and abnormal β-globin chain production, respectively. The elevation of fetal hemoglobin (HbF) can ameliorate the severity of these disorders. In sickle cell disease patients, the HbF level elevation is associated with three quantitative trait loci (QTLs), BCL11A, HBG2 promoter, and HBS1L-MYB intergenic region. This study elucidates the existence of the variants in these three QTLs to determine their association with HbF levels of transfusion-dependent Saudi β-thalassemia patients. Materials and Methods. A total of 174 transfusion-dependent β-thalassemia patients and 164 healthy controls from Eastern Province of Saudi Arabia were genotyped for fourteen single nucleotide polymorphisms (SNPs) from the three QTL regions using TaqMan assay on real-time PCR. Results. Genotype analysis revealed that six alleles of HBS1L-MYB QTL (rs9376090C p = 0.0009, rs9399137C p = 0.008, rs4895441G p = 0.004, rs9389269C p = 0.008, rs9402686A p = 0.008, and rs9494142C p = 0.002) were predominantly associated with β-thalassemia. In addition, haplotype analysis revealed that haplotypes of HBS1L-MYB (GCCGCAC p = 0.022) and HBG2 (GTT p = 0.009) were also predominantly associated with β-thalassemia. Furthermore, the HBS1L-MYB region also exhibited association with the high HbF cohort. Conclusion. The stimulation of HbF gene expression may provide alternative therapies for the amelioration of the disease severity of β-thalassemia.

Figure 1

Linkage disequilibrium (LD) analysis patterns between 3 HBG2, 4 BCL11A, and 7 HBS1L-MYB SNPs compared in thalassemia patients against control cohort. The figure illustrates the chromosome 6 loci inhabiting the seven HBS1L-MYB interregion SNPs outlining the chromosomal location, SNP ID, and the positions that were genotyped in this study. HaploView output of LD across 14 SNPs from the genotyping data in Saudi population. The pairwise correlation between the SNPs was measured as r² and shown (×100) in each diamond. Enhancer haplotypes are in red boxes and diminisher haplotypes are in blue boxes. Coordinates are according to the NCBI build dbSNP 144 Homo sapiens annotation release 107 (reference sequence NT_025741.16). Sig. SNPs: haplotypes of significant SNPs.