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

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Kate Gardner, Tony Fulford, Nicholas Silver, Helen Rooks, Nikolaos Angelis, Marlene Allman, Siana Nkya, Julie Makani, Jo Howard, Rachel Kesse-Adu, David C. Rees, Sara Stuart-Smith, Tullie Yeghen, Moji Awogbade, Raphael Z. Sangeda, Josephine Mgaya, Hamel Patel, Stephen Newhouse, Stephan Menzel, Swee Lay Thein

Original languageEnglish
Pages (from-to)235-239
Number of pages5
JournalBlood Advances
Issue number3
Early online date1 Feb 2018
Accepted/In press12 Dec 2017
E-pub ahead of print1 Feb 2018
Published13 Feb 2018


King's Authors


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 (Xmn1-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 HbSβ0 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 (r2) in the HbSS or HbSβ0 patients. The model was replicated with consistent r2 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.

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