Fetal Hemoglobin In Sickle Cell Anemia: Molecular Characterization of Saudi Patients From the Southwestern Province.

Sickle cell disease (SCD) is common in the Eastern and Southwestern (SW) Provinces of Saudi Arabia. Patients from the SW Province have many complications of this disease but they have phenotypic differences from African Americans that include a high prevalence of splenomegaly, rare CNS disease and absence of leg ulcers. In contrast, Eastern Province patients have a milder phenotype that is related to a nearly uniformly high fetal hemoglobin (HbF) level that is associated with the Saudi-Indian haplotype of the HBB gene-like cluster. SW Province patients have variable HbF levels and do not have the Saudi-Indian haplotype. We studied patients from the SW Province to determine the associations of known HbF quantitative trait loci (QTL) with HbF concentration. Seventy-seven Saudi patients, aged ≥4 yrs, with SCD were studied, 53 HbS homozygotes and 24 with HbS-β⁰ thalassemia. Their age was 17.7±10 (range 4–46) yrs and 45% were on hydroxyurea. HBB gene cluster haplotypes were 58 (75%) Benin, 17 (22%) Bantu, 1(1.5%) Senegal/Bantu, and 1(1.5%) Senegal. HbF level was measured by capillary electrophoresis and we used the lowest HbF level after age 4 yrs, the age where HbF levels stabilized, for analysis. Genotyping was done by TaqMan SNP genotyping assays, and included SNPs in BCL11A (rs4671393, rs766432), HBS1L-MYB (rs28384513, rs9399137, rs4895441), and OR51B5/6 (rs5006884). Results are summarized in the Table. QTLs showed similar trend in their effects on HbF level when patients on hydroxyurea were excluded from analysis. BCL11A was the sole QTL associated with HbF level in Saudi patients from the SW Province whereas the HBS1L-MYB and OR51B5/6 loci had no effect. For comparison, we selected cases from 2 studies of African American with SCD. All were HbS homozygotes and none took hydroxyurea, and we compared them to Saudi patients who were HbS homozygotes and not on hydroxyurea (n=29). Compared with African Americans with similar HBB haplotypes, and after adjusting for the BCL11A genotype, Saudi cases from SW Province had HbF levels almost twice that of African Americans (p <0.0001). Given that Saudi and African American patients had a nearly identical distribution of HBB gene cluster haplotypes, we examined ancestral origin of Saudi and African American patients. Using a genome-wide set of SNPs, we performed a principal component analysis with the Saudi, the African Americans with SCD and African, Arab, Asian and European populations from the Human Genome Diversity Project. We estimated the F_st statistic between these populations which is defined as the proportion of genetic diversity due to allele frequency differences among populations and can be interpreted as the distance between populations. African American cases were in close proximity to Yoruban, Mandenka and Bantu populations while Saudi patients resembled Arab populations. African American patients were the farthest from Saudi patients as compared with Asian and European populations. The commonality of HBB haplotypes in these Saudi cases and African Americans, coupled with the genetic distance between these populations suggest that genetic modifiers remote from the HBB cluster or unknown environmental influences are likely to account for the higher HbF in these Saudi patients.

No relevant conflicts of interest to declare.