Gardner, KateFulford, TonySilver, NicholasRooks, HelenAngelis, NikolaosAllman, MarleneNkya, SianaMakani, JulieHoward, JoKesse-Adu, RachelRees, David CStuart-Smith, SaraYeghen, TullieAwogbade, MojiSangeda, RaphaelMgaya, JosephinePatel, HamelNewhouse, StephenMenzel, StephanThein, Swee L2019-05-072019-05-072018http://hdl.handle.net/20.500.11810/5234Fetal hemoglobin (HbF) is a strong modifier of sickle cell disease (SCD) severity and isassociated with 3 common genetic loci. Quantifying the genetic effects of the 3 loci wouldspecifically address the benefits of HbF increases in patients. Here, we have applied statisticalmethods using the most representative variants:rs1427407andrs6545816inBCL11A,rs66650371(3-bp deletion) andrs9376090inHMIP-2A,rs9494142andrs9494145inHMIP-2B,andrs7482144(Xmn1-HBG2in theb-globin locus) to createg(HbF), a genetic quantitativevariable for HbF in SCD. Only patients aged$5 years with complete genotype and HbFdata were studied. Five hundred eighty-one patients with hemoglobin SS (HbSS) or HbSb0thalassemia formed the“discovery”cohort. Multiple linear regression modeling rational-ized the 7 variants down to 4 markers (rs6545816,rs1427407,rs66650371, andrs7482144)eachindependentlycontributing HbF-boosting alleles, together accounting for 21.8% of HbFvariability (r2) in the HbSS or HbSb0patients. The model was replicated with consistentr2in 2 different cohorts: 27.5% in HbSC patients (N5186) and 23% in 994 Tanzanian HbSSpatients.g(HbF), our 4-variant model, provides a robust approach to account for the geneticcomponent of HbF in SCD and is of potential utility in sickle genetic and clinical studiesenJournal ArticleDOI 10.1182/bloodadvances.2017009811.