Browsing by Author "Menzel, Stephan"

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    Fetal Hemoglobin is Associatedwith Peripheral Oxygen Saturation in Sickle Cell Disease in Tanzania
    (EBioMedicine, 2017) Nkya, Siana; Mgaya, Josephine; Urio, Florence; Makubi, Abel; Thein, Swee L; Menzel, Stephan; Cox, Sharon E.; Newton, Charles R; Kirkham, Fenella J; Mmbando, Bruno P; Makani, Julie
    Fetal hemoglobin (HbF) and peripheral hemoglobin oxygen saturation (SpO2) both predict clinical severity in sickle cell disease (SCD), while reticulocytosis is associated with vasculopathy, but there are few data on mechanisms. HbF, SpO2 and routine clinical and laboratorymeasureswere available in a Tanzanian cohort of 1175 SCD individuals aged ≥ 5 years and the associationwith SpO2 (as response variable transformed to a Poisson distribution) was assessed by negative binomial model with age and sex as covariates. Increase in HbF was associated with increased SpO2 (rate ratio, RR = 1.19; 95% confidence intervals [CI] 1.04, 1.37 per natural log unit of HbF; p = 0.0004). In univariable analysis, SpO2 was inversely associated with age, reticulocyte count, and log (total bilirubin) and directly with pulse, SBP, hemoglobin, and log(HbF). In multivariable regression log(HbF) (RR 1.191; 95%CI 1.04, 1.37; p = 0.013), pulse (RR 1.01; 95%CI 1.00, 1.01; p = 0.026), SBP (RR 1.008; 95%CI 1.00, 1.02; p=0.014), and hemoglobin (1.120; 95%CI 1.05, 1.19; p=0.001) were positively and independently associated with SpO2 while reticulocyte count (RR 0.985; 95%CI 0.97, 0.99; p =0.019) was independently inversely associated with SpO2. In SCD, improving SpO2, in part through cardiovascular compensation and associated with reduced reticulocytosis, may be a mechanism by which HbF reduces disease severity.
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    g(HbF): a genetic model of fetal hemoglobin in sickle cell disease.
    (Blood advances., 2018) Gardner, Kate; Fulford, Tony; Silver, Nicholas; Rooks, Helen; Angelis, Nikolaos; Allman, Marlene; Nkya, Siana; Makani, Julie; Howard, Jo; Kesse-Adu, Rachel; Rees, David C; Stuart-Smith, Sara; Yeghen, Tullie; Awogbade, Moji; Sangeda, Raphael; Mgaya, Josephine; Patel, Hamel; Newhouse, Stephen; Menzel, Stephan; Thein, Swee L
    Fetal 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 studies