Abstract
Ph.D. (Biochemistry)
The vitamin D receptor gene (VDR), together with vitamin D status, have been implicated in susceptibility to
tuberculosis (TB), numerous auto-immune diseases and several cancers. The VDR is tightly regulated and the
pathway is influenced by genetic variation, affecting function, epigenetic variation, affecting regulation, and
environment, affecting vitamin D status and VDR transactivation capacity. It is thus hypothesized that sequence
variation in the VDR and signalling partners in the vitamin D signalling pathway, together with VDR epigenetic
variation and ligand availability, influence VDR production and function.
The research conducted here commenced in 2011, as a Master’s degree (MSc.) and was upgraded to a PhD in
August 2012. The research forms an integral part of a larger project, involving other members of the research
group, to whom I am indebted to and who will receive credit throughout the thesis for contributions made to
better comprehend the ‘big picture’. The specific objectives of this larger project are all aimed to better
understand the contribution of vitamin D and the VDR to disease predisposition and cover the following
hypotheses, involving multiple techniques (Table i) and were conducted by different individuals in our
laboratory:
VDR serves as a model for the development of a bioinformatic or in silico workflow to identify regions
of interest in gene regulation and expression for studies aiming to integrate genetic and epigenetic
variation with function, as influenced by the environment (conducted by Donovan S Saccone).
VDR genetic and epigenetic variation, together with vitamin D status modulates the vitamin D signaling
pathway, contributing to tuberculosis susceptibility (conducted by V Meyer).
South Africa (SA), similar to reports on other regions in the world, shows an inverse relation between
skin-cancers (and thus a high exposure to UVB) and internal cancers, due to the protective effect of
UVB-related vitamin D production (conducted by TJ Jeffery).
The rate of the innate-immune response is individual-specific (conducted by V Meyer and BR Jones).
Inter-individual variation in TLR2 expression and autophagy markers (Beclin 1 and LC3) influence innate
immune function (conducted by BR Jones and Dr. Abhimanyu).