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

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: rs1427407 and rs6545816 in BCL11A , rs66650371 (3-bp deletion) and rs9376090 in HMIP-2A , rs9494142 and rs9494145 in HMIP-2B , and rs7482144 ( Xmn 1- HBG2 in the β-globin locus) to create g(HbF ) , 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 0 thalassemia formed the “discovery” cohort. Multiple linear regression modeling rationalized the 7 variants down to 4 markers ( rs6545816 , rs1427407 , rs66650371 , and rs7482144 ) each independently contributing HbF-boosting alleles, together accounting for 21.8% of HbF variability ( r 2 ) in the HbSS or HbSβ 0 patients. The model was replicated with consistent r 2 in 2 different cohorts: 27.5% in HbSC patients (N = 186) and 23% in 994 Tanzanian HbSS patients. g(HbF) , 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.