Homozygosity for a Haplotype in the HBG2‐OR51B4 Region is Exclusive to Arab‐Indian Haplotype Sickle Cell Anemia

Homozygosity for rs334 (GAG-GTG, glu6val) or sickle cell anemia is common in Saudi Arabia. In the Eastern Province the sickle hemoglobin (HbS) gene is usually on the autochthonous Arab Indian (AI) β-globin gene (HBB) haplotype [1]. The higher fetal hemoglobin (HbF) level in the AI haplotype is often associated with milder disease compared with other HbS-associated haplotypes, especially in children [2, 3].The Xmn1 G-A (C-T) polymorphism (rs7482144) is present in both the AI haplotype and the Senegal haplotype. Rs10128556, which is in linkage disequilibrium (LD) with rs7482144, could be the functional SNP of the Senegal haplotype [4]. The minor alleles of these SNPs also characterize the AI haplotype where adults had ~20% HbF compared with ~10% HbF in the Senegal haplotype. This suggests that elements linked to rs10128556 and rs7482144 in the AI but not the Senegal haplotype might affect HbF gene expression.We compared the genome-wide distribution of SNPs in Saudi patients with the AI haplotype and Benin haplotype. Variants distinguishing these populations were limited to chromosome 11p15.5. Annotation of these SNPs narrowed the selection to 3 that we analyzed jointly using haplotype analysis. Homozygosity for a T/A/T haplotype of rs16912979 (in HS-4 of the LCR), rs7482144 and rs10128556 was exclusive to the AI haplotype. The AI haplotype might include a functionally important sub-haplotype that accounts for high HbF.