Longitudinal Epigenome-Wide Dna Methylation and Gene Expression Signatures Associated With Incident Chronic Kidney Disease in an African Population

Objective: Chronic kidney disease is rapidly increasing in African populations, yet its molecular determinants remain poorly understood. Longitudinal epigenetic studies from African settings are scarce despite distinct genetic and environmental exposures. This study aimed to identify longitudinal DNA methylation changes associated with the development and progression of chronic kidney disease and to integrate these findings with gene expression profiles. Design and method: Genome-wide DNA methylation was measured in 548 adults at baseline and approximately six years later using a high-density methylation array. Epigenome-wide association analyses were conducted for incident chronic kidney disease, change in estimated glomerular filtration rate, and change in urinary albumin-to-creatinine ratio, adjusting for demographic, clinical, and technical factors. Differentially methylated regions were identified using region-based approaches with family-wise error rate control. Gene expression profiling was performed in a subset of participants, followed by expression quantitative trait methylation analyses to assess functional links between DNA methylation and gene expression. Results: At baseline, differentially methylated positions associated with incident chronic kidney disease and changes in kidney function were identified in genes involved in cytoskeletal organization and cellular stress responses. Region-based analyses revealed significant differentially methylated regions related to immune signaling pathways. At follow-up, additional regions associated with kidney function decline were observed, with recurrent methylation changes across time points in loci related to immune regulation and developmental control. Integrative analyses demonstrated inverse associations between DNA methylation and gene expression for several immune-related genes, supporting functional relevance. Conclusions: This longitudinal study identifies epigenetic signatures associated with the development and progression of chronic kidney disease in an African population. The integration of DNA methylation and gene expression highlights immune and kidney-related pathways that may contribute to early disease processes. These findings provide a foundation for future research on epigenetic markers for risk stratification and prevention of chronic kidney disease in African populations.