Abstract
Most sickle cell anemia (SCA) patients indigenous to the Eastern Province of Saudi Arabia have their HbS gene on the Arab-Indian (AI) HBB gene cluster haplotype. Their fetal hemoglobin (HbF) levels are near 20% and they have milder disease compared with SCA where the HbS gene is on African origin HBB haplotypes [1-9]. The AI haplotype is characterized by an Xmn1 restriction site at position 2158 5' to HBG2 (rs7482144), a Hinc2 site 5' to HBE (rs3834466) and other polymorphisms [10]. The causal elements that modify HbF might be in linkage disequilibrium with the beta(S) globin gene in this Saudi population. We first performed homozygosity mapping using genome-wide single nucleotide polymorphisms (SNPs) in AI HbS homozygotes [11,12] and identified a single large autozygous region including the HBB cluster and surrounding genes. By next generation sequencing, we examined this region in these same individuals and identified several variants that included a SNP in the HBD promoter region at position 268 bp 5' to HBD (CCAAC > TCAAC). We found this SNP only when the HbS gene was on an AI haplotype and not in SCA with other haplotypes. This SNP was functional in reporter assays in K562 cells and is an AI haplotype-specific marker.