Abstract
M.Sc.
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). TB is
a multifactorial disease, influenced by both environmental and genetic factors. Susceptibility varies
among individuals and is likely explained by differential environmental exposures and genetic factors.
For example, Africans are more susceptible to TB than non-Africans, likely attributed to their generally
lower socioeconomic status and possible higher frequencies of ‘susceptible’ genetic variants. Similarly,
males are more susceptible to TB than females, presumably as a consequence of gender-based sociocultural
differences as well as biological and/or genetic differences.
From a host genetic perspective, TB is a complex disease associated with variants from several
genes. The Vitamin D Receptor (VDR) gene, coding for the VDR protein, has received much attention as
a candidate gene; the VDR mediates vitamin D functions, of which one is to restrict M. tuberculosis
survival in macrophages. Several studies attempting to associate VDR single nucleotide polymorphisms
(SNPs) with TB susceptibility have given inconsistent results. Factors suggested to contribute to these
inconsistencies include confounding environmental factors as well as higher VDR genetic/haplotypic
diversity and less linkage disequilibrium (LD) in African populations compared to non-African
populations. However, epigenetic variation has not yet been considered as an additional confounding
factor leading to inconsistencies in genetic association studies for TB and VDR.
vi
Epigenetic factors are heritable and pivotal to regulate gene transcription. Moreover, epigenetic factors
are highly susceptible to environmental influences and have been shown to be the underlying factor in
certain disease aetiologies. Not only are epigenetic factors susceptible to environmental influences, but
also to genetic factors acting in cis or in trans. An example is the formation or elimination of a
methylatable CpG by a SNP. On the other hand, epigenetic factors may influence the genotype through
formation of methylation-induced SNPs. The synergistic effect of genetic variants, epigenetic variants and
the environment on disease is known as the common disease genetic epigenetic (CDGE) hypothesis. The
CDGE hypothesis supports the study of both genetic and epigenetic variants to provide a better
understanding of disease aetiologies and to increase the power of association studies.