Browsing by Author "Bowker, Nicholas Grant"
Now showing 1 - 1 of 1
Results Per Page
- ItemDeciphering genetic susceptibility to tuberculous meningitis(Stellenbosch : Stellenbosch University, 2016-12) Bowker, Nicholas Grant; Moller, Marlo; Kinnear, Craig; Hoal, Eileen; Salie, Muneeb; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.ENGLISH SUMMARY: Tuberculous meningitis (TBM) is a type of extrapulmonary tuberculosis (TB) which leads to inflammation of the meninges through small lesions called Rich foci. TBM represents 1% of total TB disease, with the age of onset being around 2-5 years of age. Disease development remains poorly understood, including the mechanism of dissemination across the blood-brain barrier. This study concentrated on the involvement of the host genome in TBM susceptibility. We hypothesised that multiple common variants of moderate effect size are more likely to influence TBM susceptibility than rare variants of large effect. The SAC are a 5-way admixed population with genetic contributions from European, East Asian, South Asian, Bantu-speaking African and KhoeSan groups. Two technologies were used to genotype single nucleotide polymorphisms (SNPs) of varying frequency: exome sequencing and the Illumina® Multi-Ethnic Genotyping Array (MEGA). Exome sequencing involves capture of only the protein-coding regions of the human genome, constituting approximately 1% of the genome. The depth of coverage of exome sequencing enabled the detection of coding SNPs of lower frequency (<1%) which were assessed for association with TBM susceptibility. Ten TBM cases and 10 healthy controls were exome sequenced, with all study participants being from the SAC population. Gene set association tests SKAT-O and SKAT Common Rare were used to assess the association of rare SNPs and the cumulative effect of both common and rare SNPs with susceptibility to TBM, respectively. The SKAT-O analysis included 8 322 gene sets comprising 16 728 SNPs, which did not yield any associations with TBM susceptibility. Ingenuity Pathway Analysis (IPA) of the top-hits of the SKAT-O analysis showed that NOD2 and CYP4F2 are both important in TBM pathogenesis and highlighted these as targets for future study. The SKAT Common Rare analysis included 13 270 gene sets comprised of 53 239 SNPs and was CCP110 associated (p = 5.89x10-6) with TBM susceptibility. In addition, a number of top-hit genes ascribed to the development of the central nervous system (CNS) and innate immune system regulation were highlighted. The role of common variants (>5%) in TBM susceptibility were assessed by conducting a genome-wide association study (GWAS). A total of 123 TBM cases, 400 pulmonary TB (pTB) cases and 477 healthy controls were genotyped on the MEGA array. A GWAS comparing 114 TBM cases to 395 healthy controls showed no association with TBM susceptibility. A second analysis comparing 114 TBM cases to 382 pTB cases was conducted to investigate variants associated with different TB phenotypes. No significant associations were found with progression from pTB to TBM. This study represents the first exome sequencing and GWAS of a TBM cohort and has identified a single previously undescribed association with TBM susceptibility. These results further our understanding of TBM in terms of both SNPs and genes that influence susceptibility. In addition, a number of candidate genes involved in innate immunity have been identified using IPA for further genotypic and functional investigation.