School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom.
King's College Hospital National Health Service (NHS) Foundation Trust, London, United Kingdom.
Blood Adv. 2018 Feb 13;2(3):235-239. doi: 10.1182/bloodadvances.2017009811.
Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and is associated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci would specifically address the benefits of HbF increases in patients. Here, we have applied statistical methods using the most representative variants: and in , (3-bp deletion) and in , and in , and (1- in the β-globin locus) to create , a genetic quantitative variable for HbF in SCD. Only patients aged ≥5 years with complete genotype and HbF data were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbSβ thalassemia formed the "discovery" cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers (, , , and ) each contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability () in the HbSS or HbSβ patients. The model was replicated with consistent in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. , our 4-variant model, provides a robust approach to account for the genetic component of HbF in SCD and is of potential utility in sickle genetic and clinical studies.
胎儿血红蛋白 (HbF) 是影响镰状细胞病 (SCD) 严重程度的重要因素，与 3 个常见的遗传位点相关。量化这 3 个位点的遗传效应可以明确 HbF 增加对患者的益处。在此，我们应用统计学方法，选择最具代表性的变异：位于 ， 和 上的 和 ，位于 ， 和 上的 3-bp 缺失和 ，以及位于 ，和 上的 1-（β-珠蛋白基因座内），创建了一个用于 SCD 中 HbF 的遗传定量变量 。仅研究了年龄≥5 岁且基因型和 HbF 数据完整的患者。581 名血红蛋白 SS (HbSS) 或 HbSβ 地中海贫血患者构成了“发现”队列。多元线性回归模型将 7 个变异体简化为 4 个标志物（、、、），每个标志物都有增强 HbF 的等位基因，共同解释了 HbSS 或 HbSβ 患者 HbF 变异性的 21.8%（）。该模型在 2 个不同的队列中得到了一致的复制：HbSC 患者中为 27.5%（N=186），994 名坦桑尼亚 HbSS 患者中为 23%。我们的 4 变体模型为 SCD 中 HbF 的遗传成分提供了一种稳健的分析方法，在镰状细胞遗传学和临床研究中具有潜在的应用价值。
