Full Text Available
Note: Clicking the button above will open the full text document at the original institutional repository in a new window.
Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease
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 ende...
Saved in:
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
Division of Human Genetics
2017
|
| Subjects: | |
| Tags: |
No Tags, Be the first to tag this record!
|
| _version_ | 1867613211004502016 |
|---|---|
| access_status_str | Open Access |
| author | Pule, Gift Dineo |
| author2 | Wonkam, Ambroise |
| author_browse | Pule, Gift Dineo Wonkam, Ambroise |
| author_facet | Wonkam, Ambroise Pule, Gift Dineo |
| author_sort | Pule, Gift Dineo |
| collection | Thesis |
| description | 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. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/22730 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:32:31.718Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2017 |
| publishDateRange | 2017 |
| publishDateSort | 2017 |
| publisher | Division of Human Genetics |
| publisherStr | Division of Human Genetics |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/22730 Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease Pule, Gift Dineo Wonkam, Ambroise Mowla, Shaheen Novitzky, Nicolas Human Genetics 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. 2017-01-16T13:44:50Z 2017-01-16T13:44:50Z 2016 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/22730 eng application/pdf Division of Human Genetics Faculty of Health Sciences University of Cape Town |
| spellingShingle | Human Genetics Pule, Gift Dineo Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease |
| thesis_degree_str | Doctoral |
| title | Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease |
| title_full | Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease |
| title_fullStr | Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease |
| title_full_unstemmed | Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease |
| title_short | Study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea-induced γ-globin expression in sickle cell disease |
| title_sort | study of genetic modifiers of fetal hemoglobin and mechanisms of hydroxyurea induced γ globin expression in sickle cell disease |
| topic | Human Genetics |
| url | http://hdl.handle.net/11427/22730 |
| work_keys_str_mv | AT pulegiftdineo studyofgeneticmodifiersoffetalhemoglobinandmechanismsofhydroxyureainducedgglobinexpressioninsicklecelldisease |