Epigenetic Mechanisms of Type 2 Diabetes Susceptibility in Nigerian Populations: DNA Methylation and Histone Modification Profiling

The epigenetic basis of type 2 diabetes susceptibility in sub-Saharan African populations is a critically underexplored area of metabolic disease research, and characterising disease-associated epigenetic marks in Nigerian patients may reveal population-specific mechanisms and biomarker targets not identifiable from European genomic studies. This dissertation investigates DNA methylation and histone modification profiles associated with type 2 diabetes susceptibility in Nigerian populations, combining genome-wide epigenetic profiling with targeted locus-specific analysis and functional validation. A discovery cohort of fifty type 2 diabetes patients and fifty healthy controls from Ibadan, Oyo State, underwent genome-wide DNA methylation profiling of peripheral blood mononuclear cells by enhanced reduced representation bisulfite sequencing. Differentially methylated regions were identified by bioinformatic pipeline analysis with multiple testing correction. Histone modification profiling of H3K4me3, H3K27ac, and H3K27me3 at metabolic gene regulatory regions was performed by chromatin immunoprecipitation followed by sequencing. A replication cohort of two hundred participants from Lagos and Abuja provided targeted locus-specific validation by pyrosequencing. Functional consequence of identified differentially methylated regions was assessed by transcription factor binding site analysis and correlation with target gene expression by RNA sequencing. Genome-wide analysis identified two hundred and fourteen differentially methylated regions, with significant enrichment at genes involved in insulin signalling, adipogenesis, and inflammatory pathways. Several differentially methylated regions overlap with loci not previously reported in European or East Asian type 2 diabetes epigenome-wide association studies, suggesting population-specific epigenetic susceptibility architecture. A twelve-locus methylation signature discriminates type 2 diabetes from controls in both cohorts. Keywords: epigenetics, DNA methylation, type 2 diabetes, Nigerian populations, histone modification.