g(HbF): a genetic model of fetal hemoglobin in sickle cell disease

Abstract

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: <i>rs1427407</i> and <i>rs6545816</i> in <i>BCL11A</i>, <i>rs66650371</i> (3-bp deletion) and <i>rs9376090</i> in <i>HMIP-2A</i>, <i>rs9494142</i> and <i>rs9494145</i> in <i>HMIP-2B</i>, and <i>rs7482144</i> (<i>Xmn</i>1-<i>HBG2</i> in the β-globin locus) to create <i>g(HbF</i><i>)</i>, 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 HbSβ⁰ thalassemia formed the "discovery" cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers (<i>rs6545816</i>, <i>rs1427407</i>, <i>rs66650371</i>, and <i>rs7482144</i>) each <i>independently</i> contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability (<i>r</i>²) in the HbSS or HbSβ⁰ patients. The model was replicated with consistent <i>r</i>² in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. <i>g(HbF)</i>, 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.