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

[摘要] ENGLISH ABSTRACT : In spite of the wide variety of anti-tuberculosis drugs, tuberculosis (TB),caused by mycobacterium tuberculosis (MTB), is the second leading infectiousdisease after Human Immunode ciency Virus (HIV) or Acquired Immunode ciency Syndrome (AIDS), and one of the leading causes of human deathfrom infectious diseases, especially in Sub-Saharan Africa. Approximately onethirdof the world population are latently infected with MTB, of which, 10 %progress to active TB. Obstacles in TB control include lengthy treatment regimensof more than 6 months, drug resistance, lack of an e ective vaccineand limited knowledge and incomplete information about factors that triggerthe progression of an MTB infection to disease. Moreover, the association ofTB and HIV or AIDS has also promoted all of the conditions of an explosiveincrease in TB incidence and prevalence. Several studies suggest that hostgenetic factors also a ect susceptibility and resistance to TB. Genome wideassociation study (GWAS) provides a way of examining many common variantsin di erent populations to see if any variant is associated with a trait bysearching for small variations, called single nucleotide polymorphisms (SNPs).However, it is well known that GWAS alone is insu cient to elucidate thegenetic 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 asa new paradigm to GWAS, to elucidate and analyze human genetic susceptibilityin relation to the infecting MTB by combining association signals fromGWAS and available functional and comparative genomics information for humanand MTB. We have identi ed 6 disease associated genes for the admixed South Africa coloured (SAC) population and 8 disease associated genes for thehomogeneous Ghana-Gambia population. We used a graph-based approach toestablish a relationship between these di erent disease associated genes andfront-line drug targets in relation to MTB. Furthermore, we performed GeneOntology (GO) process and pathway enrichment analyses. These yielded subnetworks,enriched processes and pathways that may play critical role in TBimmunogenicity and pathogenesis. We also investigated ancestry-speci c TBrisk in the SAC population and results revealed that the African Khomani(Sub-Kalahari San) ancestry highly contributes to disease risk in this populationobserved to be highly susceptible to TB. Several studies have beenconducted on identifying candidate genes conferring risk susceptibility to TB.However, most of these studies only analysed relationships between these genesand the host system. Here, we have also considered the pathogen system, thuscombining host, pathogen and host-pathogen protein-protein functional interactionsto examine relationships between host TB susceptibility and pathogenesis.Furthermore we perform functional relationships between identi edcandidate 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.

[发布机构] Stellenbosch University