DNA methylation patterns associated with prior tuberculosis infection in people with HIV: a pilot cross-sectional study

BackgroundMechanisms by which prior tuberculosis (TB) increases long-term risk for cancer, cardiovascular, and neurological disorders remain unclear, particularly in people with HIV (PWH). This study investigated DNA methylation (DNAm) patterns and associated pathways in PWH with and without prior TB infection. MethodsDNAm was analyzed in blood samples from 30 PWH (10 with prior latent TB infection [LTBI], 10 with previous successfully treated active TB, and 10 with no TB) using the Illumina MethylationEPIC BeadChip covering over 850,000 CpG sites. Functional enrichment analyses for Gene Ontology, KEGG pathways, and gene set enrichment analysis were performed. Statistical significance was set at a false discovery rate of <0.05. ResultsA total of 25,084 differentially methylated CpGs (dmCpGs) were identified in the prior active TB vs. no TB comparison, corresponding to 8 differentially methylated regions (DMRs) in KCNC4-DT, GRAMD1C, ZNF44, FIGN, KCNN3, and PLA2G1B genes. In the LTBI vs. no TB comparison, 7,682 dmCpGs were observed, corresponding to 18 DMRs in SPATC1L, ZFP57, KCNN3, LRSAM1, PLEKHG5, MCF2L, BRSK2, SH3GL2, AP001468.58 and STK32C genes. In both prior active TB vs. no TB and LTBI vs. no TB comparisons, DNAm changes were enriched in pathways related to neurogenesis, neuron differentiation, glutamatergic synapse, and neuroactive ligand-receptor interactions. The LTBI comparison showed additional enrichment in pathways related to synaptic membrane and serotonergic synapse. Cardiovascular pathways were specific to prior active TB, with significant enrichment in vascular smooth muscle contraction, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, and dilated cardiomyopathy pathways. Both TB groups showed enrichment in gene sets associated with lung, colorectal, gastric, and breast cancers. The prior active TB group demonstrated additional enrichment for prostate cancer and proteoglycans in cancer, while the LTBI group had additional enrichment for endometrial, esophageal, liver cancers, and Ewings sarcoma. ConclusionPrior TB infection in PWH is associated with DNAm changes in pathways related to neural function, cardiovascular health, and cancer risk suggesting epigenetic mechanisms for TB-related long-term complications.