Epigenetic Modifications in Response to Chronic Malaria Exposure and Their Relationship to Immune Regulation in Children in Benue State, North Central Nigeria

Background: Chronic Plasmodium falciparum malaria exposure in holoendemic Nigerian communities drives complex immunological adaptations that may involve epigenetic regulation of immune gene expression. DNA methylation changes at cytokine gene loci have been proposed as mechanisms underlying acquired tolerance to malaria, yet empirical data from high-burden Nigerian states such as Benue remain absent from the primary literature. Objectives: This study aims to quantify global DNA methylation levels and assess methylation at interleukin-10 and tumour necrosis factor-alpha promoter regions in peripheral blood mononuclear cells of children with varying malaria exposure histories in Benue State, and to correlate methylation patterns with cytokine production and malaria episode frequency. Methods: Sixty children aged 5 to 12 years will be stratified by confirmed malaria episode frequency over two years. Peripheral blood mononuclear cells will be isolated. LINE-1 bisulphite pyrosequencing will estimate global methylation. Cytokine promoter methylation will be quantified by quantitative methylation-specific PCR. ELISA will measure cytokine concentrations. Regression will model methylation-immune relationships. Expected Outcomes: Children with higher cumulative malaria exposure are hypothesised to exhibit differential methylation at interleukin-10 promoters associated with elevated anti-inflammatory cytokine expression, reflecting tolerance mechanisms. Conclusion: Findings will fill a gap in the epigenetic immunophysiology of malaria in Nigeria. Keywords: epigenetics, DNA methylation, malaria immunity, cytokines, Benue State.