Abstract
Patients with sickle cell disease (SCD) from the Southwestern (SW) Province of Saudi Arabia have variable fetal hemoglobin (HbF) levels and have HBB gene cluster haplotypes of African origin. We studied 77 patients, aged 17.7 +/- 10 (range 4-46) years (69% HbS homozygotes and 31% HbS-beta(0) thalassemia), to determine the associations of known HbF quantitative trait loci (QTL) with HbF concentration. HBB gene cluster haplotypes were 74% Benin, 22% Bantu, and 4% others. Genotyping Single nucleotide polymorphism (SNPs) in BCL11A, HBS1L-MYB, and OR51B5/6 showed that BCL11A was the sole QTL associated with HbF level. We compared these findings with two studies of African American with SCD. After adjusting for the BCL11A genotype, Saudi cases from the SW Province had HbF levels almost twice that of African Americans (P < 0.0001). When we examined the genetic population structure of the African Americans and Saudi patients using genome-wide data, we found that African Americans were similar to Yoruban, Mandenka, and Bantu Africans while Saudi patients resembled Arab populations. The commonality of HBB haplotypes coupled with the genetic distance between these populations suggests that genetic modifiers remote from the HBB cluster or unknown environmental influences are likely to account for the higher HbF in these Saudi patients.