Polymorphisms in the regulatory region of the Vitamin D Receptor gene (VDR): in silico analysis, tuberculosis association and functional impact

M.Sc.Tuberculosis, of which the causative agent is Mycobacterium tuberculosis, presents itself as a serious health problem globally, especially in Africa. Susceptibility to this infectious disease is influenced by the virulence of the strain of mycobacteria, environmental factors, and genetic variation within the host. The Vitamin D Receptor gene or VDR has been identified as a candidate gene for TB susceptibility. This gene codes for the VDR protein that mediates the biological actions of the active form of vitamin D. Vitamin D has been shown to impair growth of Mycobacterium tuberculosis in human monocytes and macrophages. Vitamin D also provides a link between Toll-like receptor activation and the antibacterial responses of innate immunity in its production of cathelicidin. The VDR protein is a transcription factor that mediates the effects of the active form of vitamin D. Vitamin D has an immunomodulatory role and variations in the VDR gene may result in variations in the functioning of the VDR protein, and hence variations in response to infection. The VDR gene includes the largely non-coding 5’ regulatory region exons 1a-1f and the coding exons 2-9. As a result of increased awareness of the heritability of gene expression and reports of disease associations with VDR promoter region variants, the focus of the research described in this dissertation was the regulatory region of the VDR gene. Polymorphisms that occur within the regulatory region were viii investigated, as were the effects these polymorphisms may have on gene expression, influencing host susceptibility to tuberculosis, with an emphasis on African populations. VDR polymorphisms have been shown to be involved in susceptibility to tuberculosis, particularly the FokI SNP in exon 2, BsmI and ApaI in intron 8 and the synonomous TaqI in exon 9. However, results have been inconsistent. SNPs shown to be associated with TB may serve as markers of truly functional SNP with which they are in linkage disequilibrium (LD). The majority of these association studies involve single nucleotide polymorphisms (SNPs) found in the introns or are silent mutations in the coding exons. Variations in the 5’ regulatory region have been shown to affect gene expression, in particular if they influence the binding sites of transcription factors