Fetal hemoglobin in sickle cell anemia: Genetic studies of the Arab-Indian haplotype

• Published in: Blood cells, molecules, & diseases Vol. 51; no. 1; pp. 22 - 26
• Main Authors: Ngo, Duyen, Bae, Harold, Steinberg, Martin H., Sebastiani, Paola, Solovieff, Nadia, Baldwin, Clinton T., Melista, Efthymia, Safaya, Surinder, Farrer, Lindsay A., Al-Suliman, Ahmed M., Albuali, Waleed H., Al Bagshi, Muneer H., Naserullah, Zaki, Akinsheye, Idowu, Gallagher, Patrick, Luo, Hong-yuan, Chui, David H.K., Farrell, John J., Al-Ali, Amein K., Alsultan, Abdulrahman
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2013
• Subjects: Adolescent; Adult; Alleles; Anemia, Sickle Cell - genetics; Anemia, Sickle Cell - metabolism; Arabs - genetics; BCL11A; beta-Globins - genetics; beta-Globins - metabolism; Carrier Proteins - genetics; Child; Child, Preschool; Fetal hemoglobin; Fetal Hemoglobin - genetics; Fetal Hemoglobin - metabolism; Genes, myb; GTP-Binding Proteins - genetics; Haplotype; Haplotypes; Hemoglobin, Sickle - genetics; Hemoglobin, Sickle - metabolism; Homeodomain Proteins - genetics; HSP70 Heat-Shock Proteins - genetics; Humans; Kruppel-Like Transcription Factors; Locus Control Region; Middle Aged; Mutation; Nuclear Proteins - genetics; Peptide Elongation Factors - genetics; Polymorphism, Genetic; Promoter Regions, Genetic; Sequence Analysis, DNA; Sickle cell; Transcription Factors - genetics; Young Adult; BCL11A; Haplotype; Sickle cell; Fetal hemoglobin
• ISSN: 1079-9796; 1096-0961
• DOI: 10.1016/j.bcmd.2012.12.005

Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3–4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefore studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and employed targeted genotyping of polymorphic sites to explore cis- and trans- acting elements associated with high HbF expression. We also described sequences which appear to be unique to the AI haplotype for which future functional studies are needed to further define their role in HbF modulation. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation in HbF. KLF1 polymorphisms associated previously with high HbF were not present in the 44 patients tested. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remains unexplained by the genetic loci that we studied. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.