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

Abstract

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 therefor studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and known genotyped cis- and trans-acting elements associated with HbF expression. 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 of HbF. KLF1 polymorphisms associated previously with high HbF were not present In the 44 patients tested. The SNPs and genetic loci we have chosen for this study do not explain the high HbF in sickle cell patients with AI haplotype or its variation among patients with this haplotype. 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.

High Hemoglobin F in a Saudi Child Presenting with Pancytopenia

“…These observations suggest that there are perhaps environmental or other genetic elements that could be linked to these haplotypes that affect HbF genes (HBG1and HBG2) transcription, thus increasing the levels of HbF [1]. A large study conducted in Saudi Arabia concluded that certain regulatory elements that are yet to be discovered, modulate the effects of the known cis-and trans-acting regulators may be responsible for the higher levels of HbF in the AI haplotype [3].…”

“…In SCD patients, high levels of HbF were found to be protective. The level of HbF in Saudi haplotype or Arab-Indian (AI) haplotype of SCD is 3-4 folds higher than that in the African haplotype [3]. Comparison of the levels of HbF in many different haplotypes including the regions; Africa, the Middle East, and the Indian subcontinent, showed the Senegal and the Saudi haplotypes had the highest levels of HbF compared to the Bantu and Benin haplotypes, which had the lowest levels [1].…”

“…HbF protects against many of the clinical complications of sickle cell disease (SCD), because of its ability to hinder the polymerization of deoxygenated hemoglobin S (HbS) [2,3].…”

Computed Tomography Findings in the Spleen of Sickle Cell Patients in Saudi Arabia.

“…Reports from the Eastern Province of Saudi Arabia and gulf region showed that spleen function is usually preserved in patients with sickle cell anemia (SCA) who presented with levels of Hb F higher than 20% and had a high prevalence of alpha thalassemia trait. Ngo et al, 2013;Wali et al, 2002) This study was conducted to see the abnormal splenic finding among patients with sickle cell disease in Al-Ahsa, aregion in the Eastern Province of Saudi Arabia. The study documented different splenic pathologies that were found among 119 patients.…”

A New <b><i>Trans</i></b>-Acting Modulator of Fetal Hemoglobin?

“…However, homozygosity for minor alleles at rs16912979, rs7119428, and rs7482144 (T/A/T), which are in the major regulatory region of the HBB gene cluster, was present exclusively in the AI haplotype and might represent a functional cis-acting domain modulating HBG2 expression [4]. BCL11A and MYB, the 2 known trans-acting QTL accounted for only 8.8% of HbF variance in the AI haplotype population, suggesting the likelihood of other trans-acting elements whose polymorphisms could account for the varying levels of HbF [5]. To further examine this possibility, whole-genome sequencing was carried out in 14 highly selected adults with the AI haplotype, 7 with HbF of 8.2% and 7 with HbF of 23.5%.…”