Vitamin D, genetic variation of the vitamin D pathway and methylation of the vitamin D receptor gene : functional impact on the innate immune response to the mycobacterial lipopeptide Pam₃CSK₄

Ph.D. (Biochemistry)Abstract: 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)