Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease
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.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.identifier.apacitation | Pule, G. D. (2016). <i>Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease</i>. (Thesis). University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics. Retrieved from http://hdl.handle.net/11427/22730 | en_ZA |
dc.identifier.chicagocitation | Pule, Gift Dineo. <i>"Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease."</i> Thesis., University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2016. http://hdl.handle.net/11427/22730 | 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.ris | TY - Thesis / Dissertation AU - Pule, Gift Dineo AB - 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. DA - 2016 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2016 T1 - Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease TI - Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease UR - http://hdl.handle.net/11427/22730 ER - | en_ZA |
dc.identifier.uri | http://hdl.handle.net/11427/22730 | |
dc.identifier.vancouvercitation | Pule GD. Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease. [Thesis]. University of Cape Town ,Faculty of Health Sciences ,Division of Human Genetics, 2016 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/22730 | en_ZA |
dc.language.iso | eng | |
dc.publisher.department | Division of Human Genetics | en_ZA |
dc.publisher.faculty | Faculty of Health Sciences | en_ZA |
dc.publisher.institution | University of Cape Town | |
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 | Doctoral Thesis | |
dc.type.qualificationlevel | Doctoral | |
dc.type.qualificationname | PhD | en_ZA |
uct.type.filetype | Text | |
uct.type.filetype | Image | |
uct.type.publication | Research | en_ZA |
uct.type.resource | Thesis | en_ZA |
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