Browsing by Author "Gebremariam, Zoe Zerihun"

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    An integrated framework modelling susceptibility to tuberculosis in homogeneous and admixed populations
    (Stellenbosch : Stellenbosch University, 2016-12) Gebremariam, Zoe Zerihun; Mazandu, Gaston K.; Stellenbosch University. Faculty of Science. Dept. of Mathematical Sciences
    ENGLISH ABSTRACT : In spite of the wide variety of anti-tuberculosis drugs, tuberculosis (TB), caused by mycobacterium tuberculosis (MTB), is the second leading infectious disease after Human Immunode ciency Virus (HIV) or Acquired Immunode ciency Syndrome (AIDS), and one of the leading causes of human death from infectious diseases, especially in Sub-Saharan Africa. Approximately onethird of the world population are latently infected with MTB, of which, 10 % progress to active TB. Obstacles in TB control include lengthy treatment regimens of more than 6 months, drug resistance, lack of an e ective vaccine and limited knowledge and incomplete information about factors that trigger the progression of an MTB infection to disease. Moreover, the association of TB and HIV or AIDS has also promoted all of the conditions of an explosive increase in TB incidence and prevalence. Several studies suggest that host genetic factors also a ect susceptibility and resistance to TB. Genome wide association study (GWAS) provides a way of examining many common variants in di erent populations to see if any variant is associated with a trait by searching for small variations, called single nucleotide polymorphisms (SNPs). However, it is well known that GWAS alone is insu cient to elucidate the genetic structure of a complex disease and may lead to non conclusive results. In this thesis, we use a post association analysis, which has been suggested as a new paradigm to GWAS, to elucidate and analyze human genetic susceptibility in relation to the infecting MTB by combining association signals from GWAS and available functional and comparative genomics information for human and MTB. We have identi ed 6 disease associated genes for the admixed South Africa coloured (SAC) population and 8 disease associated genes for the homogeneous Ghana-Gambia population. We used a graph-based approach to establish a relationship between these di erent disease associated genes and front-line drug targets in relation to MTB. Furthermore, we performed Gene Ontology (GO) process and pathway enrichment analyses. These yielded subnetworks, enriched processes and pathways that may play critical role in TB immunogenicity and pathogenesis. We also investigated ancestry-speci c TB risk in the SAC population and results revealed that the African Khomani (Sub-Kalahari San) ancestry highly contributes to disease risk in this population observed to be highly susceptible to TB. Several studies have been conducted on identifying candidate genes conferring risk susceptibility to TB. However, most of these studies only analysed relationships between these genes and the host system. Here, we have also considered the pathogen system, thus combining host, pathogen and host-pathogen protein-protein functional interactions to examine relationships between host TB susceptibility and pathogenesis. Furthermore we perform functional relationships between identi ed candidate genes and front-line drug targets based on these functional networks. This may enhance our understanding about TB susceptibility and pathogenesis, and enhance research for TB drug and vaccine development.