| Literature DB >> 29437638 |
Kate Gardner1,2, Tony Fulford3, Nicholas Silver1, Helen Rooks1, Nikolaos Angelis1, Marlene Allman2, Siana Nkya4, Julie Makani4, Jo Howard5, Rachel Kesse-Adu5, David C Rees1,2, Sara Stuart-Smith2,6, Tullie Yeghen7, Moji Awogbade2, Raphael Z Sangeda4, Josephine Mgaya4, Hamel Patel8,9, Stephen Newhouse8,9,10, Stephan Menzel1, Swee Lay Thein1,2.
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: 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.Entities:
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Year: 2018 PMID： 29437638 PMCID： PMC5812320 DOI： 10.1182/bloodadvances.2017009811
Source DB: PubMed Journal: Blood Adv ISSN： 2473-9529