Center of Excellence in Sickle Cell Disease, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Blood Cells Mol Dis. 2013 Jun;51(1):22-6. doi: 10.1016/j.bcmd.2012.12.005. Epub 2013 Mar 7.
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.
镰状细胞贫血在中东和印度很常见，在这些地区，HbS 基因有时与阿拉伯-印度（AI）β-球蛋白基因（HBB）簇单倍型相关。在这种镰状细胞贫血的单倍型中，胎儿血红蛋白（HbF）水平比那些具有非洲起源的 HbS 单倍型的患者高 3-4 倍。对于调节 AI 单倍型患者中 HbF 的遗传因素知之甚少。因此，我们研究了具有 AI 单倍型的沙特 HbS 纯合子（平均 HbF 为 19.2±7.0%，范围为 3.6 至 39.6%），并采用了多态性位点的靶向基因分型来探索与高 HbF 表达相关的顺式和反式作用元件。我们还描述了似乎仅存在于 AI 单倍型的序列，需要进一步进行未来的功能研究以进一步确定它们在 HbF 调节中的作用。所有病例，无论 HbF 浓度如何，均为 HBB 顺式的 AI 单倍型特异性元件纯合子。在其他人群中与 HbF 相关的 BCL11A 和 HBS1L-MYB 的 SNPs 仅解释了 HbF 变异的 8.8%。在 44 名测试的患者中未发现先前与高 HbF 相关的 KLF1 多态性。具有 AI 单倍型的镰状细胞贫血患者中，超过 90%的 HbF 变异无法用我们研究的遗传位点来解释。AI 单倍型患者中 HbF 水平的离散度表明，其他遗传因素调节着已知的顺式和反式作用调节剂的作用。这些调节元件仍有待发现，它们可能在沙特和其他一些 HbF 水平特别高的人群中具有特异性。
