An integrated framework modelling susceptibility to tuberculosis in homogeneous and admixed populations

Gebremariam, Zoe Zerihun (2016-12)

Thesis (MSc)--Stellenbosch University, 2016

Thesis

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.

AFRIKAANSE OPSOMMING : Ten spyte van die wye verskeidenheid van anti-tuberkulose dwelms, tuberkulose (TB), wat veroorsaak word deur Mycobacterium tuberculosis (MTB), is die tweede grootste aansteeklike siektes ná Menslike Immuniteitsgebrekvi- rus (MIV) of Verworwe Immuniteitsgebreksindroom (VIGS), en een van die grootste oorsake van menslike dood van aansteeklike siektes, veral in Sub- Sahara Afrika. Ongeveer een derde van die wêreld se bevolking is sluimerend besmet is met MTB, waarvan, 10 % vordering aktiewe TB. Struikelblokke in TB beheer sluit in langbehandelingsregimes van meer as 6 maande, weerstand teen die medikasie, 'n gebrek aan 'n doeltre ende entstof en beperkte kennis en onvolledige inligting oor faktore wat die verloop van 'n MTB infeksie teen siektes veroorsaak. Daarbenewens het die vereniging van TB en MIV of vigs ook bevorder al die voorwaardes van 'n plofbare toename in TB voorkoms en die voorkoms. Verskeie studies dui daarop dat gasheer genetiese faktore ook 'n invloed vatbaarheid en weerstand teen TB. Genoom wye assosiasie studie (GWAS) bied 'n manier om die behandeling van baie algemene variante in verskillende bevolkings om te sien of enige variant is wat verband hou met 'n eienskap deur te soek vir klein variasies, genoem enkele nukleotied polimor smes (SNPs). Dit is egter bekend dat GWAS alleen onvoldoende is om die genetiese struktuur van 'n komplekse siekte toe te lig en kan lei tot nie afdoende resultate. In hierdie tesis, gebruik ons 'n post vereniging analise, wat as 'n nuwe paradigma te GWAS het voorgestel, om toe te lig en te ontleed menslike genetiese vatbaarheid met betrekking tot die besmet MTB deur die kombinasie van assosiasie seine van GWAS en beskikbaar funksionele en vergelykende genomika inligting vir menslike en MTB. Ons het 6 siekte geassosieer genevir die venmeng Suid-Afrika gekleurde (SAC) bevolking en 8 siekte geassosieer gene vir die homogene Ghana-Gambië bevolking geïdenti seer. Ons gebruik 'n gra ek gebaseerde benadering tot 'n verhouding tussen die verskillende siektes wat verband hou gene en tussen siekte gene en front-line dwelm teikens te stel met betrekking tot MTB. Verder het ons uitgevoer Gene Ontologie (GO) proses en pad verryking ontleed. Hierdie opgelewer sub-netwerke, verryk prosesse en roetes wat kritieke rol kan speel in die TB immunogenisiteit en patogenese. Ons ondersoek ook afkoms spesi eke TB risiko in die SAC bevolking en resultate het getoon dat die Afrikaanse Khomani (Sub-Kalahari San) afkoms hoogs dra by tot siekte risiko in hierdie bevolking waargeneem hoogs vatbaar vir TB te wees. Verskeie studies is gedoen op die identi sering van kandidaat gene wat die risiko vatbaarheid vir TB verleen. Maar die meeste van hierdie studies het net ontleed verhoudings tussen hierdie gene en die gasheer stelsel. Hier het ons ook gekyk na die patogeen stelsel, dus die kombinasie van gasheer, patogene en gasheer-patogeen proteïen-proteïen funksionele interaksies om verhoudings tussen gasheer TB vatbaarheid en patogenese is oorweeg. Verder voer ons funksionele verwantskappe tussen geïdenti seer kandidaat gene en voorste lyn dwelm mikpunte gebaseer op hierdie funksionele netwerke. Dit kan ons begrip oor TB vatbaarheid en patogenese verbeter, en verbeter navorsing vir TB dwelm en entstof ontwikkeling.

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