Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease

 

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dc.contributor.advisor Wonkam, Ambroise en_ZA
dc.contributor.advisor Mowla, Shaheen en_ZA
dc.contributor.advisor Novitzky, Nicolas en_ZA
dc.contributor.author Pule, Gift Dineo en_ZA
dc.date.accessioned 2017-01-16T13:44:50Z
dc.date.available 2017-01-16T13:44:50Z
dc.date.issued 2016 en_ZA
dc.identifier.citation Pule, G. 2016. Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease. University of Cape Town. en_ZA
dc.identifier.uri http://hdl.handle.net/11427/22730
dc.description.abstract Sickle Cell Disease (SCD) is a growing global problem with firm roots in sub-Saharan Africa (SSA) representing over 3/4 of the global burden of the disease. The prevalence of the sickle mutation (HbS) in SSA has been amplified by the partial resistance to Plasmodium falciparum malaria, which is endemic along tropical equatorial Africa. Several genetic variants have since been associated with fetal hemoglobin (HbF), the disease-ameliorating globin protein, including variants at three principal loci; BCL11A, HBS1L-MYB intergenic polymorphisms (HMIP1/2) and the β-globin gene cluster, which together account for 10 - 20% HbF variance in SCD patients. Similarly, numerous signalling pathways have been implicated in the regulation of γ-globin expression, however, a complete understanding of the regulation of HbF remains elusive. The overall aims of this project were: 1a) to investigate the known variants in key HbF-promoting loci such as BCL11A erythroid-specific enhancer, BCL11A, HBS1L-MYB intergenic polymorphism (HMIP1/2), the β-globin gene cluster, as well as the influence of the co-inheritance of 3.7kb alpha globin gene deletion in a cohort of SCD patients from Cameroon; and 1b) to validate novel HbF-promoting loci reported in 2 genome-wide association studies (GWAS) carried out in a population of Sardinians (Italy) and SCD patients from Tanzania and explore the influence of known promoter variants in SAR1 associated with HbF in African American patients amongst Cameroonian SCD patients; 2) to investigate the molecular mechanisms of hydroxyurea (HU)-induced production of HbF using a primary erythroid cell model from hematopoietic stem cells (HSCs) derived from umbilical cord blood and lastly, 3) to investigate the prevalence of SCD-related polymorphisms; β-globin gene haplotype, HbS mutation and malaria-resistance variants in 3 SCD-unaffected (HbAA) cohorts from South Africa, Zimbabwe and Malawi. en_ZA
dc.subject.other Human Genetics en_ZA
dc.title Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease en_ZA
dc.type Thesis / Dissertation en_ZA
uct.type.publication Research en_ZA
uct.type.resource Thesis en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Division of Human Genetics en_ZA
dc.type.qualificationlevel Doctoral en_ZA
dc.type.qualificationname PhD en_ZA
uct.type.filetype Text
uct.type.filetype Image


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